“Antibiotics and corticosteroids: Indications and approaches”

Raymond Cross, M.D., M.S., AGAFAssociate Professor of Medicine

Director of the Inflammatory Bowel Disease ProgramUniversity of Maryland School of Medicine

Co-Director, Digestive Health CenterUniversity of Maryland Medical Center

12/4/14

Goals of Therapy

• Induce remission• Maintain steroid-free remission• Enhance quality of life• Achieve mucosal healing• Prevent/treat complications of disease• Avoid short and long term toxicity of therapy

PGA of Disease Activity

• Remission: No symptoms• Mild disease activity: No limitations in activity (i.e.,

not missing work, not canceling social engagements)

• Moderate disease activity: Impaired activity (i.e., missing days of work, canceling some social engagements)

• Severe disease activity: Severely impaired activity (i.e., housebound, bathroom bound, hospitalized)

AMINOSALICYLATES

AMINOSALICYLATE DISTRIBUTION

5-ASA Content of 5-ASA Preparations Generic Trade 5-ASA Content

(%)Usual Dosage Amount of 5-

ASA DeliveredSulfasalazine Azulfidine,

Azulfidine EN, Sulfazine, Sulfazine EC

38 4 g 1.6 g

Mesalamine Apriso, Asacol HD, Canasa, Delzicol, Lialda, Pentasa, Rowasa, SfRowasa,

100 2.4-4.8 g 2.4-4.8 g

Balsalazide Colazal, Giazo 35 3.3-6.75 g 1.2 g-2.4 g

Olsalazine Dipentum 100 1 g 1 g

Adapted from: Ulcerative Colitis-The Complete Guide to Medical Management (Lichtenstein)

Oral 5-ASA Are Effective For Induction Of Remission In UC

Cochrane Database of Systematic Reviews17 OCT 2012 DOI: 10.1002/14651858.CD000543.pub3http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD000543.pub3/full#CD000543-fig-00101

No Difference in Remission Rates between 5-ASA Preparations

Cochrane Database of Systematic Reviews17 OCT 2012 DOI: 10.1002/14651858.CD000543.pub3http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD000543.pub3/full#CD000543-fig-00401

High Dose Oral 5-ASA is Not More Effective at Induction of Remission than Moderate Dose in UC

Cochrane Database of Systematic Reviews17 OCT 2012 DOI: 10.1002/14651858.CD000543.pub3http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD000543.pub3/full#CD000543-fig-00501

High Dose 5-ASA May Be More Effective in Patients Exposed to Prior Therapy

Oral 5-ASA Rectal therapies Steroids ≥2 meds0

1020304050607080

64 61 54 5870 70 64 70

Treatment Success at Week 6 in Patients Having Taken Previous UC Therapy

2.4 g/day 4.8 g/day

Perc

ent o

f Pati

ents

Sandborn, W. J., et al. (2009). Gastroenterology

P=0.05 P=0.01

Efficacy of Once vs. Twice Daily 5-ASA for Induction of Remission in UC

Series105

10152025303540

Clinical and Endoscopic Remission at Week 8

MMX BID MMX QD Placebo

Perc

ent o

f Pati

ents

Lichtenstein, G. R., et al. (2007). Clin Gastroenterol Hepatol

ORAL VERSUS RECTAL MESALAMINE VERSUS COMBINATION THERAPY IN ACTIVE DISTAL

ULCERATIVE COLITIS

Dose of Oral 5-ASA Not Important For Maintenance of Remission in UC

Cochrane Database of Systematic Reviews17 OCT 2012 DOI: 10.1002/14651858.CD000544.pub3http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD000544.pub3/full#CD000544-fig-00501

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

5-ASA is Not Protective Against Colon Cancer in IBD

• Meta-analysis of non-referral populations– 4 studies included

• Association between ≥ 1 year of 5-ASA use and neoplasia

• aOR 0.95 (0.7-1.4)• Significant heterogeneity among trials

Nguyen, G. C., et al. (2012). Am J Gastroenterol

Budesonide MMX 9 mg Effective at Induction of Remission in UC

Remission Response Symptom Resolution05

10152025303540

7.4

24.816.517.9

33.328.5

13.2

30.6 28.9

12.1

33.925

Combined Clinical and Endoscopic Remission at Week 8

Placebo (n=121) MMX 9 mg (n=121) MMX 6 mg (n=123)5-ASA 2.4 g (n=123)

Perc

ent o

f Pati

ents

*

*

*

16

*

Sandborn et al, Gastroenterology. 2012*p<0.05

Budesonide Foam Effective for Treatment of UP and UPS

Remission Rectal Bleeding=0 Endoscopy Score ≤1

0

10

20

30

40

50

60

42.250.3

55.8

31.8 35.746.8

BFPlacebo

Perc

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f Pati

ents

5-A

SA E

xpos

ed S

ub-G

roup *

*

P<0.05Sandborn, WJ. ACG 2014

ORAL BUDESONIDE IN ACTIVE CROHN’S DISEASE

CD Maintenance Therapy with Budesonide

0

10

20

30

40

50

60

70

3 months 6 months 9 months 12 months

Perc

ent

of p

atie

nts

rela

psin

g

6mg/day

3mg/day

placebo

p<0.01

p<0.05

*

**

Sandborn, W et al. Am J Gastroenterol 2005

Long Term Use of Budesonide is Well Tolerated

0 6 12 18 24

Budesonide -0.43 -0.5 -0.5 -0.5 -0.5

Prednisolone -0.43 -0.73 -0.75 -0.8 -0.8

-0.85-0.75-0.65-0.55-0.45-0.35-0.25-0.15-0.05

Budesonide Prednisolone

MonthsT-score

T-sc

ore

P=0.015 P=0.007 P=0.008 P=0.011

Schoon, EJ. et al. Clin Gastroenterol Hepatol 2005

Corticosteroid Therapy for UC

*30 days after initiating corticosteroid therapy

Complete Remission

54%(n = 34)

PartialRemission

30%(n = 19)

Immediate Outcome*(n = 63)

1-YearOutcome(n = 63)

Steroid Dependent

22%(n = 14)

Prolonged Response

49%(n = 31)

Surgery 29%

(n = 18)

NoResponse

16%(n = 10)

Faubion, W., et al. Gastroenterology 2001

Corticosteroid Therapy for Crohn’s Disease

*30 days after initiating corticosteroid therapy

Complete Remission

58%(n = 43)

PartialRemission

26%(n = 19)

Immediate Outcome*(n = 74)

1-YearOutcome(n = 74)

Steroid Dependent

28%(n = 21)

Prolonged Response

32%(n = 24)

Surgery 38%

(n = 28)

NoResponse

16%(n = 12)

Faubion, W., et al. Gastroenterology 2001

IV Steroids

• No need to give more than 60 mg of Methylprednisolone sodium succinate or 300 mg of hydrocortisone

• Can give once daily• Response generally occurs within 5-7 days!• ~60% of patients completely respond to IV

steroids

Truelove, SC and Jewell, DP. Lancet 1974Truelove, SC et al. Lancet 1978Jarnerot, G et al. Gastroenterology 1985Gustavsson, A et al. Am J Gastroenterol 2007

Use of Steroids with IFX for Induction of Remission is Highly Effective in CD

Week 14 Week 500%

10%20%30%40%50%60%70%80%90%

IFX+MTX IFX+Placebo

Percent of Pa-tients

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

IV Steroids Premedication Reduces ATI in CD

ATI Level ATI +05

1015202530354045

Placebo HC

Perc

ent o

f Pati

ents

P=0.02

P=0.06

Farrell, R. J., et al. Gastroenterology 2003

Conclusions• 5-ASA is effective for induction and maintenance of

remission in patients with UC• Combination of oral and topical 5-ASA more effective

for distal disease• 5-ASA is of marginal benefit in patients with CD• All 5-ASA are effective when given at equal dose• Moderate and high dose 5-ASA equally effective for

induction of remission in UC• Once daily dosing is equally effective to split dosing

(and likely associated with better adherence)

Conclusions (cont.)

• Budesonide is effective for induction of remission in mild to moderate ileocolonic Crohn’s disease and UC– Has a limited role in maintenance of remission

• Prednisone is effective at induction of remission– Poor side effect profile– No role for maintenance of remission– May be used in combination with an anti-TNF to induce

remission in moderate to severe Crohn’s disease• IV steroids may be used prior to IFX to decrease ATI