Optimal Use of Immunomodulators and Biologicsuniverse-syllabi.gi.org/acg2013_38_slides.pdf ·...

3/17/2014

1

Edward V. Loftus, Jr., M.D.

Professor of Medicine

Division of Gastroenterology and Hepatology

Mayo Clinic

Rochester, Minnesota, U.S.A.

Optimal Use of Immunomodulators and Biologics

Loftus Disclosures (last 12 months)

• Consultant •Abbott Labs

•UCB Pharma

•Janssen Biotech

•Takeda

• Research support • Abbott Labs

• UCB Pharma

• Bristol-Myers Squibb

• Shire

• Genentech

• Janssen Biotech

• Amgen

• Pfizer

• Braintree Labs

• Millennium-Takeda

• Santarus

• GlaxoSmithKline

• Robarts Clinical Trials

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Overview

• Existing treatment paradigms • Thiopurine

• Anti-TNF agents

• Evolving paradigms • Role of AZA monotherapy?

• Treat earlier in the course of Crohn’s

• Use objective evidence of inflammation to base treatment decisions

• Use objective evidence to follow up on treatment changes

• Use drug monitoring when available

©2010 MFMER | slide-3

Existing Treatment Paradigms


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3

Oral 5-ASAs • Mesalamine 1.5–4.8 g/d • Balsalazide 6.75 g/d • Sulfasalazine 4–6 g/d

Extensive (pancolitis)

Rectal 5-ASA

Ind

ucti

on

5-ASA, AZA/6-MP, IFX/ADA

Oral steroid

IV steroid

Kornbluth A, Sachar D. Am J Gastroenterol 2010;105:501-23. Ordas I, Eckmann L, et al. Lancet 2012;380:1606-19.

Management of Mild to Moderate UC

Infliximab, Adalimumab

Main

t

± 1st-Line

2nd-

Line

3rd-Line

Azathioprine for Steroid-Dependent, Active UC

0 5-ASA 3.2 g per day

(in 3 divided doses†)

AZA 2 mg/kg/d

Pati

en

ts (

%)

20

30

40

50

60

10

Steroid-Free Clinical/Endoscopic Remission* After 6 Months

P=.006

53%

19%

*Defined as clinical remission (Powell-Tuck Index Score of 0) and endoscopic remission (Baron Index

Score 1) plus steroid discontinuation. Patients treated with concurrent tapering dose of steroids. †0.8 g

at breakfast and lunch and 1.6 g at dinner.

Ardizzone S et al. Gut 2006;55:47-53.

• 25% AE rate

in AZA group

• 6% had to

discontinue

AZA

3/17/2014

4

6

11

34

26 28

36

0

5

10

15

20

25

30

35

40

8 Weeks 30 WeeksP

erc

en

t o

f P

ati

en

ts

Placebo IFX 5 mg/kg IFX 10 mg/kg

Infliximab for UC: ACT 1 and ACT 2 Clinical Remission

15 16 17

39

34 35

32

37

34

0

5

10

15

20

25

30

35

40

45

8 Weeks 30 Weeks 54 Weeks

Pe

rce

nt

of

Pa

tie

nts

Placebo IFX 5 mg/kg IFX 10 mg/kg

§ †

†

† P 0.002 vs placebo ‡ P 0.003 vs placebo

§ P = 0.001 vs placebo

†

‡

‡

‡

‡

ACT 1 ACT 2

Rutgeerts P et al. N Engl J Med 2005;353:2462-76

§ §

ACT1/2 Trials: Survival Free of Colectomy

Sandborn WJ et al, Gastroenterology 2009;137:1250-60.

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5

UC Success: AZA vs. IFX vs. AZA+IFX for Moderate to Severe UC: Week 16

24%

50%

37%

22%

69%

55%

40%

77%

63%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

Steroid-freeremission

Response Mucosal healing

AZA

IFX

AZA + IFX

**

*

*

* *

* P < 0.05 vs AZA

** P<0.05 vs AZA and vs IFX

Panaccione R et al, DDW 2011 Oral Presentation #835.

Conclusion: IFX+AZA superior to both AZA and IFX monotherapy in inducing

steroid-free remission

Cyclosporine vs. Infliximab for Acute Severe UC

• 110 patients steroid refractory UC

• Treatment failure • No response day 7

• No steroid-free remission day 98

• Relapse between days 7 and 98

• Colectomy

• Death

• SAE: CyA 16%, IFX 25%

• Conclusion: CyA was not superior to IFX in acute severe UC

54% 60%

0%

10%

20%

30%

40%

50%

60%

70%

80%

Infliximab Cyclosporine

Treatment Failure, %

Laharie D, et al. Lancet 2012;380:1909-15.

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Adalimumab for Moderate to Severe UC: Induction/Maintenance Trial (n=494)

9.3%

34.6% 31.7%

16.5%

50.4%

41.1%

0%

10%

20%

30%

40%

50%

60%

Week 8 Endpoints

Placebo

ADA

8.5%

18.3% 15.4% 17.3%

30.2% 25.0%

0%

10%

20%

30%

40%

50%

60%

Week 52 Endpoints

Placebo

ADA

Sandborn WJ et al, Gastroenterology 2012;142:257-65.

*

*

*

*

* *

Golimumab (GLM) for Moderate to Severe Ulcerative Colitis, PURSUIT Studies

31.4

47.1 50.6

Maintenance of Clinical Response Among

Responders

29.7

51.8 55

Induction of Clinical Response

Sandborn WJ et al, Gastroenterology 2013 (online early).

Doi:10.1053/j.gastro.2013.05.048.

Sandborn WJ et al, Gastroenterology 2013 (online early).

Doi:10.1053/j.gastro.2013.06.010.

* *

* P < 0.01 vs placebo

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Ind

ucti

on

AZA/MTX, Anti-TNF, Natalizumab

Prednisone, Budesonide

AZA/6MP/MTX

Lichtenstein GR, Hanauer SB, Sandborn WJ. Am J Gastroenterol 2009;104:465-83.

Baumgart DC, Sandborn WJ. Lancet 2012;380:1590-1605.

Management of Crohn’s Disease

Anti-TNF (Infliximab,

Adalimumab, Certolizumab pegol

Main

t

Natalizumab

Updated Meta-Analysis of AZA/6-MP for Crohn’s Disease: Benefit Is Not So Clear

Induction of Remission

Prevention of Relapse

Khan KJ et al, Am J Gastroenterol 2011;106:630-42.

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3002233-15

Methotrexate for Crohn’s Disease

• Methotrexate 25 mg/week IM/SC (and

possibly 15 mg/week orally) is effective for

inducing remission in patients with steroid-

dependent and steroid-refractory active CD

• Methotrexate 15-25 mg/week IM/SC is

effective for maintenance of remission and

steroid sparing in CD

• Less “lymphomagenic” than thiopurines?

Construct of Biologic Agents Used in Crohn’s

Disease

Murine Chimeric

Infliximab

IgG1 isotype

75% human

Humanized

CDP571

Natalizumab

IgG4 isotype

95% human

Human

Recombinant

Receptor/Fc

Fusion Protein

Etanercept

(p75)

Onercept (p55)

100% human

Pegylated

Humanized

CDP870

Certolizumab

IgG4 isotype

95% human

Human

D2E7

Adalimumab

IgG1 isotype

100% human

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0

20

40

60

80

100

* p<0.05

NS Non-significance

4

25

* NS 48

1. Schreiber et al. Gastroenterology. 2005 Sep;129(3):807-18

2. Sandborn et al. N Engl J Med 2007

3. Hanauer et al. Gastroenterology 2006;130:323-333

4. Targan et al. N Engl J Med 1997;337:1029-1035

Certolizumab Certolizumab

Pegol1 Pegol2 Adalimumab3 Infliximab4

7

27

*

10

*

21

* NS

12

24

36

Induction of Clinical Remission at Week 4 In Crohn’s Disease:

Certolizumab, Adalimumab, Infliximab

% o

f P

ati

en

ts

n 57 60 231 243 74 75 76 25 27 28

Tx Pbo CzP

400mg

Pbo CzP

400mg

Pbo ADA

80/40mg

ADA

160/80mg

Pbo INF

5mg/kg

INF

10mg/kg

Delta 20 11 12 24 44 21

Infliximab – ACCENT I2 Certolizumab Pegol – PRECISE 21

Adalimumab - CHARM3

28.6 18.3

64.1

47.9

30.7

0

20

40

60

80

100

Open-label

Induction

Week 6

Week 26

remission

Net

remission

week 26

% o

f P

ati

en

ts

Pbo CzP

21.0 12.3

58.5

39.0

22.8

0

20

40

60

80

100

Open-label

Induction

Week 2

Week 30

remission

Net

remission

week 30

% o

f P

ati

en

ts

Pbo IFX

17.0 9.9

58.0

40.0

23.2

0.0

20.0

40.0

60.0

80.0

100.0

Open Label

Induction

Week 4

Week 26

remission

Net

remission

week 26

% o

f P

ati

en

ts

Pbo ADA

Certolizumab Pegol – PRECISE 14

18.3 29.5

0

20

40

60

80

100

Net

remission

week 26

% o

f P

ati

en

ts

Pbo CzP

1. Schreiber et al. New Engl J Med 2007;357:239-250 2. Hanauer et al. Lancet 2002;359:1541-49

3. Colombel et al. Gastroenterology 2007;132:52-65 4. Sandborn et al. New Engl J Med 2007;357:228-38

Net Remission at Six Months: Certolizumab, Adalimumab, Infliximab

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P=0.056, NS

8/61 0/61

Pati

en

ts (

%)

P<0.001

Primary End Point

Mucosal Healing With Adalimumab in CD (EXTEND)

Rutgeerts P et al. Gastroenterology 2012;142:1102.

ITT, intent-to-treat; NS, not significant

13.1%

27.4% 24.2%

0

0

50

Week 12 ITT Week 52 ITT

ADA QOW (40 mg)

17/62 15/62

40

30

20

10

ADA induction (160/80 mg)/placebo

Natalizumab (Anti-Alpha 4 Integrin) Therapy for Crohn’s Disease

• Monoclonal antibody to alpha 4

integrin

• Target molecules are VCAM-1 and

MAdCAM-1

• Blocks lymphocyte trafficking from

vascular space to tissues

• Effective for induction and

maintenance of response and

remission and steroid-sparing

Villablanca EJ et al, Gastroenterology 2011;140:1776-84.

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ENACT-2 Natalizumab in Active Crohn’s Disease:

Maintenance of Clinical Response (70 points) in Week 12

Responders

37

24

30

22

67

59 55 55

0

10

20

30

40

50

60

70

80

At Week 36 At Week 60 At Week 36 At Week 60

Placebo

Natalizumab

Perc

en

t

Response Remission

*

* * *

*P ≤ 0.001 Sandborn WJ et al, N Engl J Med 2005; 353:1912-25

Natalizumab-Related Progressive Multifocal Leukoencephalopathy

• Reactivation of the human JC polyoma virus

• Severe neurologic disability or death

• Has occurred in 395 patients out of approximately

118,100 treated as of August 2013

• All but two cases occurred in MS patients (less

than 2% of natalizumab use in US is for Crohn’s)

• FDA mandated risk management program (TOUCH)

• Risk stratified by JC virus serology

• Use restricted to patients who have failed anti-TNF

therapy

• Must be administered as monotherapy (without other

immunosuppressive agents)

Communication with Biogen Idec Pharmaceuticals, 2013

Kleinschmidt-DeMasters BK et al, J Neuropathol Exp Neurol 2012;7:604-17.

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12

Evolving Treatment Paradigms Diminishing Role of Thiopurine Monotherapy?


AZA Is No Better Than Placebo For Early Crohn’s Disease

Ste

roid

-Fre

e R

em

iss

ion

, %

p = 0.48


• Prospective multicenter Spanish

double-blind placebo-controlled

trial (n = 131)

• Early Crohn’s (<8 weeks) with

active inflammation on

endoscopy or MRE

• Primary endpoint: steroid-free

remission at 76 weeks

• Steroids tapered by 10 mg/week

till 20 mg and then 5 mg/week

• SAE: AZA, 20.6% vs 11.1% in

placebo group

Panes J et al, Gastroenterology 2013;145:766-774

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AZA vs Conventional Management for Early Crohn’s Disease: GETAID

• Prospective multicenter French randomized open-label trial (n=132)

• Early Crohn’s (<6 mo) with risk factors for “disabling disease”: age<40, perianal disease, steroids within 3 months of diagnosis

• AZA 2.5 mg/kg/day vs conventional rx (give AZA only for steroid dependency, chronic active disease with flares, poor steroid response, or severe perianal disease)

• Primary endpoint: %trimesters in steroid-free and anti-TNF-free remission over next 3 years


Cosnes J et al, Gastroenterology 2013;145:758-65.

• Primary endpoints: AZA 67% vs.

conventional management 56%

(p=0.69)

• No difference in need for surgery

or steroids or anti-TNF therapy

Evolving Treatment Paradigms Treat Earlier in the Course of Crohn’s Disease


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14

D’Haens G et al. Lancet 2008;371:660.

(%)

P≤0.001 P=0.006 P=0.028 P=0.797 P=0.431

Clinical remission (CDAI <150), off corticosteroids, and no intestinal resection

N=133

Top-Down vs Step-Up: Early Infliximab or Standard Therapy

50 47 42

36 33

57

45

62 60 65

0

20

40

60

80

100

Wk 14 Wk 26 Wk 52 Wk 78 Wk 104

Step-Up

Top-Down

SONIC: Corticosteroid-Free Clinical Remission at Week 26

Primary Endpoint

30.6

44.4

56.8

0

20

40

60

80

100

Pro

po

rtio

n o

f P

ati

en

ts (

%)

AZA + placebo IFX + placebo IFX+ AZA

p<0.001

p=0.009 p=0.022

52/170 75/169 96/169

Colombel JF, et al. N Engl J Med 2010;362:1383-1395.

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Evolving Treatment Paradigms Treatment Decisions Based on Objective Evidence


CDAI Versus CDEIS During Treatment With Prednisolone

• Complete lack of correlation between CDAI (primarily symptom-based) and endoscopic inflammation

• Symptoms and signs of Crohn’s are neither sensitive nor specific

Modigliani R et al, Gastroenterology 1990;98:811-8.

r = 0.13; p = NS

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Is It Really “Loss of Response” or “Non-Response”?

Are Symptoms Due to IBD?

• Celiac disease

• Bacterial overgrowth

• Bile salt diarrhea

• Irritable bowel syndrome

• Hypersensitivity colitis

• Short bowel syndrome

• Carbohydrate malabsorption (lactose and fructose)

Bacterial Overgrowth in Crohn’s Disease (n=153)

• Hydrogen glucose breath test in symptomatic patients

– Increased stool frequency, increased flatulence or pain

• 25% had positive breath tests

• Risk factors

–Multiple resections

–Partial colonic resection

– Ileocolonic disease

Klaus J et al, BMC Gastroenterol 2009;9:61

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The Intersection Between Disease Assessment and Application of Therapy:

SONIC: Corticosteroid-Free Clinical Remission at Week 26 by Baseline Endoscopy Status

*Unable to determine

Pro

po

rtio

n o

f P

ati

en

ts (

%)

30.4

40.7

21.4

50.5

33.3 38.2

61.3

40.0

57.1

0

20

40

60

80

100

Lesions (n=325) No Lesions (n=93) No Endoscopy orUTD* (n=90)

AZA + placebo (n=170) IFX + placebo (n=169) IFX + AZA (n=169)

p<0.001

p=0.003 p=0.117

p=0.927

p=0.372 p=0.688

p=0.003

p=0.139 p=0.074

35/115 50/99 68/111 11/27 12/36 12/30 6/28 16/28 13/34

Colombel JF, et al. N Engl J Med 2010;362:1383-1395.

Paradigm Shift for Making Treatment Decisions in Patients with Inflammatory Bowel Disease

• OLD: Treat based on symptoms – But: symptoms are insensitive and non-specific for

bowel inflammation

• NEW: Treat based on objective markers of inflammation

– Serologic (CRP reduction)

– Endoscopic (mucosal healing)

– Radiographic (CTE/MRE improvement)

– Goal should be “mucosal healing” or absence/reduction in inflammation

– This will be the only way we can hope to alter the natural history of Crohn’s disease

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Evolving Treatment Paradigms Treatment Endpoint Based on Objective Evidence Not

Symptoms


Mucosal Healing After Treatment as Predictor of Subsequent

Disease Course in Crohn’s Disease: Norway

MH, mucosal healing

Patients with MH at 1 year

Patients without MH at 1 year

Pro

po

rtio

n o

f C

D

Pa

tie

nts

No

t R

es

ec

ted

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5 6 7

Time in Years After 1-Year Visit

Frøslie KF et al. Gastroenterology. 2007;133:412.

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Steroid Avoidance Had More Endoscopic Healing at 2 Years

Secondary End Point of the Top-Down/Step-Up Trial

P=0.0028

D’Haens G, et al. Lancet 2008;371:660. Baert FJ, et al. Gastroenterology 2010;138:463.

Pa

tie

nts

(%

)

0

100

Step-up

80

60

40

20

Top-down

Complete endoscopic healing at 2 years

30

73

Simple endoscopic score 0

Simple endoscopic score 1–9

…and these patients did better in the next 2 yrs!

Pa

tie

nts

In

R

em

iss

ion

(%

)

0 Remission

Off Steroids

80

60

40

20

Off Steroids, No Anti-TNF

70.8

27.3

62.5

18.2

Levels of CRP Are Associated With Mucosal Healing

P=0.03 P=0.02

Me

dia

n C

RP

(m

g/L

)

Jurgens M et al. Clin Gastroenterol Hepatol 2011;9:421.

Retrospective analysis of clinical and endoscopic outcomes from

serial CRP measurements in 718 CD patients receiving infliximab

0

14

12

8

4

2

10

6

No Healing

Partial Healing

Complete Healing

11.5

3.1 3.2

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CT Enterography Healing: Equivalent to Mucosal Healing at Endoscopy?

Resolution of intramural inflammation on maintenance infliximab

3/25/2005 10/11/2006

Bruining DH, et al. Clin Gastroenterol Hepatol 2011;9:679-83.

r = 0.61 p < 0.001

Radiographic Improvement on MR Enterography

Correlates With Endoscopic Improvement:

Δ MaRIA- Δ CDEIS at Week 12

Ordas I, et al. Gastroenterology 2011;140(5 Suppl 1):S73 (DDW 2011).

Courtesy of Ingrid Ordas, M.D.

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21

• Primary target: absence of mucosal ulceration

• Level of target may be influenced by comorbidities and drug-related risks

• Desired target should be maintained indefinitely

• Use both symptoms and objective measures of inflammation (endoscopic or radiologic) to guide treatment decisions

• Assess mucosal healing every 6 months till target is achieved, then every 1-2 years after, adjust according to degree of inflammation

Implementing “Treat to Target” in IBD: Mucosal Healing as the Target

Bouguen G, et al. Clin Gastroenterol Hepatol 2013 (online early). Doi:10.1016/j.cgh.2013.09.006. 41

A Proposed Algorithm for Disease Monitoring in IBD

Baseline assessment of disease activity by endoscopy paired with surrogate marker

3-6 months Re-assessment of disease

activity directly or with surrogate marker

Choice of initial therapy based on severity and prognosis of patient

Healing Documented?

Yes No

Clinical follow-up

No

Adjust therapy

Discussion with patient treatment options

Is patient willing to proceed with your recommendations?

Yes 3-6 months

Clinical follow-up that includes assessment of disease stability

6-12 months

If no other treatment options left

Slide compliments of David T. Rubin, MD

3/17/2014

22

Challenges to Mucosal Healing in Crohn’s Disease

• It can’t be achieved in many/most patients

• Unclear how much healing is really needed to affect outcomes

• It is unknown what incremental healing can be achieved by dose escalation or switching therapies

• We don’t know the appropriate time interval between changes in therapy and subsequent reassessment

• Can surrogates of endoscopic healing be used?

Evolving Treatment Paradigms Therapeutic Drug Monitoring


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23

Sies C et al. NZ Med J 2005;118(1210):1324-30.

TPMT Activity in 407 New Zealand Patients

Wild type

Homozygous

mutation

Heterozygous

mutation

0%

20%

40%

60%

80%

100%

6-TGN QUARTILES

Fre

qu

en

cy o

f R

esp

on

se

41%

78%

n=44

0-173

n=42

174-235

n=43

236-367

n=44

368-1203

P< 0.001

Target 6-TGN Level to Optimize Efficacy: >235

Dubinsky MC, et al. Gastroenterology 2000;118(4):705-13

Odds Ratio 5.0 for

treatment response

when 6-TGN > 235

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Author & Year Patients (Remission)

6TGN Threshold

Fraction Above

Threshold Remission

Fraction Below

Threshold Remission

Odds Ratio

95% Confidence

Interval

Dubinsky 2000 92 (30) 235 .78 .40 5.07 2.62-9.83

Gupta 2001 101 (47) 235 .56 .43 1.65 0.73-3.75

Belaiche 2001 28 (19) 230 .75 .65 1.62 0.26-10.2

Cuffari 2001 82 (47) 250 .86 .35 11.63 3.78-35.7

Goldenberg 2004 74 (15) 235 .24 .18 1.47 0.47-6.42

Achkar 2004 60 (24) 235 .51 .22 3.80 1.17-12.4

Pooled Estimate

0.62 (0.43-0.80)

0.36 (0.25-0.48)

3.27 1.71-6.27

Meta-Analysis: Association Between 6-TGN Levels and Clinical Remission

Osterman MT, et al. Gastroenterology 2006:130(4);1047-1053

Non-Responders Responders

0

10000

20000

30000

40000

§ p=0.0057

Non-Responders Responders

-200

0

200

400

600

* p=0.0003

Median change in 6-TGN Median change in 6-MMP

Suboptimal 6-TGN Production Correlates With 6-MP Resistance

Dubinsky MC et al, Gastroenterology 2002;122(4):904-15.

N=37 N=14 N=37 N=14

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Allopurinol Therapy for Preferential 6-MMP Metabolism

Pre-allopurinol Post-allopurinol

Sparrow MP, et al. Aliment Pharmacol Ther 2005;22:441.

Allopurinol 100 mg added; 6-MP/AZA dose reduced to 25% to 50% of baseline

0

50

100

150

200

250

300

350

400

450

6-TG

0

2000

4000

6000

8000

10000

12000

6-MMP

15

69

28

75

0

10

20

30

40

50

60

70

80

Undetectable Detectable

Remission

Endoscopic Improv.

% o

f p

atie

nts

P<0.001

Seow CH, et al. Gut 2010;59:49-54.

Detectable Serum Trough IFX Concentration is Associated with Higher Remission Rate and Endoscopic Improvement

in UC Patients

Undetectable serum IFX predicted an increased risk for colectomy (55% vs 7%; p<0.001)

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26

Karmiris K, et al. Gastroenterology. 2009;137:1628.

1.0

0.8

0.6

0.4

0.2

0.0

Pat

ien

ts w

ith

Su

stai

ne

d

Clin

ical

Re

spo

nse

(%

)

0 30 60 90 120 150 180 210 240 Sustained Clinical Response (weeks)

Log Rank: P=0.01

ADA TR>0.33 µg/mL, n=104

ADA TR<0.33 µg/mL, n=16

ADA Trough Above 0.33 µg/mL Predicts Clinical Response

Factors Affecting the Pharmacokinetics of Monoclonal Antibodies

Impact on Pharmacokinetics

Presence of ADAs

• Decreases serum mAbs

• Threefold-increased clearance

• Worse clinical outcomes

Concomitant use of IS

• Reduces formation

• Increases serum mAbs

• Decreases mAb clearance

• Better clinical outcomes

High baseline TNF-α • May decrease mAbs by increasing

clearance

Low albumin • Increases clearance

• Worse clinical outcomes

High baseline CRP • Increases clearance

Body size • High BMI may increase clearance

Gender • Males have higher clearance

Ordas I, et al. Clin Pharmacol Ther 2012;91:635. mAB, monoclonal antibody; ADA, antidrug antibody

3/17/2014

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Elevating Infliximab Concentration From Subtherapeutic Levels Is Effective in

Regaining Response in HACA (-) Patients

Clinical Outcomes of Patients with Detectable Antibodies to Infliximab or Subtherapeutic Infliximab Concentrations

Response to Test

Complete/ Partial

Response (%) P value

Detectable HACA

Increase infliximab

1/6 (17) <0.004

Change anti-TNF 11/12 (92)

Subtherapeutic concentration

Increase infliximab

25/29 (86) <0.016

Change anti-TNF 2/6 (33)

Afif W et al. Am J Gastroenterol 2010;105:1133.

HACA, human antichimeric antibody

Conclusions

• AZA, 6-MP and MTX are steroid-sparing

agents

• Anti-TNF agents are effective for inducing and maintaining response/remission in Crohn’s (IFX, ADA, CZP) and UC (IFX, ADA, GLM)

• Anti-TNF agents can reduce the need for hospitalizations and surgeries in Crohn’s and UC

• Natalizumab is an option for Crohn’s disease patients who are anti-TNF refractory, but carries a risk of PML

3/17/2014

28

Conclusions

• Several new studies suggest that azathioprine

therapy may not be effective as we once

thought

• Still has an important role in improving efficacy of

anti-TNF therapy

• Use objective markers of inflammation rather

than symptoms to make treatment decisions

• Follow up on changes in therapy with

objective markers of inflammation

• Use drug monitoring when available

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