Evidence-based Medicine: Treatment of Crohn’s Disease

Raymond Cross, MD, MS, AGAF Professor of Medicine Director, IBD Program

University of Maryland School of Medicine Co-Director Digestive Health Center

University of Maryland Medical Center Millie Long, MD, MPH

Assistant Professor of Medicine University of North Carolina

Disclosures

• Abbvie: Research grants, participation in advisory boards, and consulting

• Janssen: Participation in advisory boards

• Takeda: Consulting

• UCB: Consulting

Goals of Therapy

• Induce clinical remission (absence of symptoms)

• Avoid short and long term toxicity of therapy

• Maintain steroid-free remission

– Avoid repeated courses of steroids

• Enhance quality of life

• Prevent/treat complications of disease

• Achieve mucosal healing (“deep remission”)

• Decrease unnecessary health care expenditures (ER visits, hospitalizations, etc.)

Pentasa reduces CDAI compared to placebo

Clinical Gastroenterology and Hepatology 2004; 2:379-388

Copyright © 2004 American Gastroenterological Association Terms and Conditions

5-ASA Associated with Small Clinical Benefit in Crohn’s Disease

Rifaximin-extended Intestinal Release in Patients with Crohn’s Disease

43

54

62*

47

0

10

20

30

40

50

60

70

Pe

rce

nt

of

Pat

ien

ts in

Clin

ical

R

em

issi

on

Placebo 400 bid 800 bid 1200 bid

Prantera, C et al. (2012) Gastroenterology *p=0.005 compared to placebo

Short and Long Term Response to Prednisone

Faubion, WA, Jr., et al. (2001) Gastroenterology

ORAL BUDESONIDE IN ACTIVE

CROHN’S DISEASE

AZATHIOPRINE AS

MAINTENANCE THERAPY FOR

CROHN’S DISEASE

Early Azathioprine vs. Conventional Management

Cosnes, J, et al. (2013) Gastroenterology

Early Azathioprine in Newly Diagnosed CD

Characteristics Placebo (n=63) Azathioprine (n=68)

Steroid-free Remission at Week 76 (Primary Endpoint)

23 (37%) 30 (44%)

Patients Needing Steroids 40 (64%) 34 (50%)

Mean Days of Steroids 64+/-58 47+/-74

Development of Fistula 5 (8%) 6 (9%)

Internal Penetrating Disease 3 (5%) 4 (6%)

Perianal Fistulizing Disease 2 (3%) 2 (3%)

Patients Hospitalized 5 (8%) 11 (16%)

CD-related Surgery 1 (2%) 1 (1%)

Panés, J, et al. (2013) Gastroenterology

METHOTREXATE FOR ACTIVE

CROHN’S DISEASE

Feagan, BG, et al. (2000) N Engl J Med

Moderate-to-Severe CD: Maintenance of Remission with MTX

• Multicenter, randomized, controlled trial

• 76 steroid-dependent patients

• In remission following MTX 25 mg x 16 weeks

• Randomized to MTX 15 mg or placebo x 40 weeks

30

0 4 12 28 16 20 8 24 32 36 40

Weeks since Randomization

80

70

100

90

60

50

40

Rem

issio

n (

%)

MTX

Placebo

n=40

65%

n=36

39%

0

20

40

60

80

100

Infliximab 5 mg/kg (ACCENT I)

Certolizumab 400 mg 4-weekly (PRECiSE 2)

Adalimumab 40 mg EOW (CHARM)

Week 26–30

Long Term Maintenance of Remission in CD

N = 113 N = 113 N = 215 N = 215

Remission (CDAI<150)

N = 172 N = 172

Response (Δ100)

Reduction (≥ 70 pts and

≥ 25% in CDAI)

Pe

rce

nt

of

Pat

ien

ts

21 17 29 36 26 27

Placebo

51 52

63

39 40 48

Accent II-Fistula Response at Week 54

23 19

46

36

0

5

10

15

20

25

30

35

40

45

50

Fistula Response Complete Response

Pe

rce

nt

of

Pat

ien

ts

Placebo IFX

* *

* p<0.05

Sands, B. E., et al. (2004). N Engl J Med

Early Combined Therapy Associated with Better Short Term Results

0

10

20

30

40

50

60

70

14 26 52 78 104

Pe

rce

nt

of

pat

ien

ts

Weeks

Early combined IS group Conventional group

* * *

* p<0.05

D'Haens, G., et al. (2008). Lancet

Early Biologic Treatment Results in Higher Rates of Endoscopic Healing at 2 Years

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

P=0.0028

D'Haens, G., et al. (2008). Lancet 371(9613): 660-667. Baert, F., et al. (2010). Gastroenterology 138(2): 463-468; quiz e410-461.

Pati

en

ts (

%)

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!

Pati

en

ts I

n

Rem

issio

n (

%)

0 Remission

Off Steroids

80

60

40

20

Off Steroids, No Anti-TNF

70.8

27.3

62.5

18.2

Comparative Effectiveness Study in CD (SONIC)

Colombel, J.F., et al. N Engl J Med. 2010;362(15):1383-1395

Pati

en

ts (

%)

P=.02

P<.001

P=.06 P=.006

P=0.02

P<.001

51/170 75/169 96/169 18/109 28/93 47/107 P

ati

en

ts (

%)

30.0%

44.4%

56.8%

16.5%

30.1%

43.9%

100

0 AZA + PBO

IFX + PBO

IFX + AZA

AZA + PBO

IFX + PBO

IFX + AZA

Clinical Remission Mucosal Healing

90

80

70

60

50

40

30

20

10

100

0

90

80

70

60

50

40

30

20

10

PBO = placebo; IFX = infliximab.

0

20

40

60

80

100

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Weeks

MTX Placebo

No Benefit of MTX in Addition to Steroids and IFX for CD

Feagan, B. G., et al. (2014). Gastroenterology

n= 63/group

Pati

en

ts i

n r

em

issio

n [

%]

Prednisone

taper week 0-14

Treatment failure week 14: 24% IFX/MTX, 22% IFX

Treatment failure week 50: 44% IFX/MTX, 43% IFX

Vedolizumab in CD: Second Induction Study

Clinical Remission (CDAI ≤150) at Week 10 (Secondary Endpoint)

Sands, B. E., et al. (2014). Gastroenterology 147(3): 618-627 e613.

.

GEMINI II: Vedolizumab in Crohn’s Disease Through Week 52, Maintenance ITT

Sandborn, W. J., et al. (2013). N Engl J Med 369(8): 711-721.

Ustekinumab Induction Therapy for Anti-TNF Experienced Patients (UNITI-1)

7%

20% 16%

34%

21%

38%

0%

5%

10%

15%

20%

25%

30%

35%

40%

Remission Response

Pe

rce

nt

of

Pat

ien

ts

Placebo 130 mg 6 mg/kg

Feagan, B. G., et al. (2016). N Engl J Med 375(20): 1946-1960.

Ustekinumab Induction Therapy for Treatment Refractory Patients (UNITI-2)

20%

32% 31%

47% 40%

58%

0%

10%

20%

30%

40%

50%

60%

70%

Remission Response

Pe

rce

nt

of

Pat

ien

ts

Placebo 130 mg 6 mg/kg

Feagan, B. G., et al. (2016). N Engl J Med 375(20): 1946-1960.

Clinical Remission at Week 44 after Treatment with Ustekinumab (IM-UNITI)

26%

44% 39%

57%

41%

63%

0%

10%

20%

30%

40%

50%

60%

70%

Remission (UNITI-1) Remission (UNITI-2)

Pe

rce

nt

of

Pat

ien

ts

Placebo 90 q 12 90 q 8

Feagan, B. G., et al. (2016). N Engl J Med 375(20): 1946-1960.

Use of Therapeutic Drug Levels to Guide Changes in Therapy

Response to Test

Clinical Response

P value

Detectable HACA

Increase IFX 17% P<0.004

Change Anti-TNF

92%

Subtherapeutic concentration

Increase IFX 86% P<0.016

Change Anti-TNF

33%

Afif, W., et al. (2010). Am J Gastroenterol 105(5): 1133-1139.

IFX Dosed Based on TDM vs. Clinically Based Dosing of IFX: TAXIT

66 69

0

10

20

30

40

50

60

70

80

90

100

Pe

rce

nt

of

Pat

ien

ts

Clinical and biological remission at one year

CB

LB

N=111/126 N=115/126

Vande Casteele, N., et al. (2015). Gastroenterology 148(7): 1320-1329 e1323.

29% of patients had an IFX level below 3 mcg/ml at baseline; remission rate increased from 65 to 88% (p=0.020) after one time dose optimization

IFX Reduces Post-operative Recurrence after Intestinal Resection

0

10

20

30

40

50

60

70

80

90

100

Placebo IFX

End

osc

op

ic R

ecu

rre

nce

Rat

e

Regueiro, M., et al. (2009) Gastroenterology

Endoscopic Recurrence: endoscopic scores of i2, i3, or i4

The PREVENT Trial: Trends favoring IFX were observed for fewer clinical (wk76, wk104) and endoscopic (wk76) recurrences but the primary endpoint of clinical recurrence

was not met

Prevent: Clinical Outcomes at Week 76

Regueiro, M., et al. (2016). Gastroenterology 150(7): 1568-1578

Endoscopic Surveillance After Resection is Associated with Decreased Endoscopic Recurrence

51%

33%

49%

67%

0%

10%

20%

30%

40%

50%

60%

70%

80%

Active Care (n=122) Standard Care (n=52)

Pe

rce

nt

of

Pat

ien

ts w

ith

En

do

sco

pic

Re

curr

en

ce a

t 1

8

mo

s.

Active Care (n=122) Standard Care (n=52)p=0.03

De Cruz, P., et al. (2015). Lancet 385(9976): 1406-1417.

P=0.03

AGA Clinical Pathway for CD:

Stratifying Patients by Risk for Disabling Course

Low risk Limited anatomic involvement

Age at diagnosis >30 years

Superficial ulcerations at

endoscopy

No prior surgery

Non-stricturing, non- penetrating

disease

High risk

AGA = American Gastroenterological Association. Sandborn, W.J., et al. Gastroenterology. 2014;146(1):85-95.

Extensive anatomic involvement

Deep ulcers

Age at diagnosis <30 years

Perianal disease and/or severe rectal

disease

History of prior resection

Complicated disease behavior

AGA Clinical Pathway for CD:

Initial Treatment

Low-risk patient

Ileum and/or proximal colon, none to minimal symptoms Options • Budesonide 9 mg/d with or

without AZA • Tapering course of prednisone

with or without AZA

Diffuse or left colon, none to minimal symptoms Option • Tapering course of prednisone with

or without AZA

Moderate/high-risk patient

Options • Anti-TNF monotherapy over no therapy

or thiopurine monotherapy • Anti-TNF + thiopurine over thiopurine

monotherapy or anti-TNF monotherapy • Methotrexate for patients who do not tolerate

purine analog in combination with anti-TNF

Sandborn, W.J., et al. Gastroenterology. 2014;146(1):85-95

Conclusions

• Limited role for use of antibiotics and aminosalicylates in treatment of CD

• Steroids are useful for induction of remission in CD

• Immune suppressants, particularly MTX, are effective for maintaining steroid-induced remission in CD – Little to no evidence that earlier use of these agents improves outcomes

• Anti-TNF agents are effective for treatment of luminal and perianal CD – Early combination therapy is most effective

– Outcomes can be improved with TDM

– Prevent post-operative recurrence

• Vedolizumab and ustekinumab also effective for treatment of CD – Not yet clear how to position these agents

• AGA Care Pathways available to guide selection of optimal patient for biologic treatment (not proven to improve clinical outcomes)