Practical Use of Steroids In IBDPractical Use of Steroids In IBD

William J. Sandborn, MDMayo Clinic

Rochester, Minnesota

Steroids In IBDSteroids In IBD

•Ulcerative colitis–Rectal

• Conventional steroids

• Budesonide–Oral–IV

•Crohn’s Disease–Oral conventional steroids

–Oral budesonide

Hydro

corti

sone0

20

40

60

80

100

TOPICALGLUCOCORTICOIDS

SYSTEMIC GLUCOCORTICOIDS

Derendorf H. 1998

CLEARANCE (L/h) ORAL BIOAVAILABILITY (%)

Predniso

lone

Triamcin

oloneac

etonide

Budesonide

Flunisolid

eFlutic

asone

propionate

Methylp

redniso

loneDex

ameta

sone

Corticosteroid PharmacokineticsCorticosteroid Pharmacokinetics

Sidney Truelove, Green College,Oxford University, 1996

Sidney Truelove, Green College,Oxford University, 1996

Study Number Duration Steroid Remission P

Dose Steroid Placebo Value

Truelove 40 1 wk hydrocortisone

100 mg 55% 5% 0.01

Lennard- 39 3 wk prednisolone

Jones 5 mg 56% 9% < 0.01

Watkinson 19 2 wk hydrocortisone

100 mg 90% 11% < 0.05

Rectal Administration of Systemically Active Corticosteroids for Mildly to Moderately Active UC

Truelove. BMJ 1958; Lennard-Jones. Gut 1962; Watkinson. BMJ 1958

Meta-Analysis of Conventional Corticosteroid Enemas versus 5-ASA Enemas for Induction of Symptomatic Remission in Active

Distal UC

Meta-Analysis of Conventional Corticosteroid Enemas versus 5-ASA Enemas for Induction of Symptomatic Remission in Active

Distal UC

CP985036-11

Marshall:Marshall:Gut, 1997Gut, 1997

0.10.1 1.01.0 10.010.0 100.0100.0

CampieriCampieri

Corticosteroids betterCorticosteroids better Odds ratioOdds ratio 55--ASA betterASA better

FriedmanFriedman

Danish 5Danish 5--ASAASAstudy groupstudy group

FarupFarup

LeeLee

PooledPooled

Study Number DurationBudesonideBudesonide Placebo P

Dose Remission Remission Value

Hanauer 233 6 weeks 0.5 mg7% 4% NS

2.0 mg 19% 4% <0.05

8.0 mg 27% 4% <0.001

Hanauer. Gastroenterology 1998

Budesonide Enemas for Mildly to Moderately Active UC

Meta-Analysis of Conventional Corticosteroid Enemas versus Budesonide Enemas for All Outcomes in Active Distal UC

Meta-Analysis of Conventional Corticosteroid Enemas versus Budesonide Enemas for All Outcomes in Active Distal UC

CP985036-9

Marshall:Marshall:Gut, 1997Gut, 1997

ImprovementImprovement

Symptomatic (n=1)Symptomatic (n=1)

EndoscopicEndoscopic (n=4)(n=4)

Histological (n=4)Histological (n=4)

RemissionRemission

Symptomatic (n=2)Symptomatic (n=2)

EndoscopicEndoscopic (n=4)(n=4)

Histological (n=2)Histological (n=2)

0.10.1 1.01.0 10.010.0 100.0100.0ConventionalConventionalcorticosteroids bettercorticosteroids better Pooled odds ratioPooled odds ratio BudesonideBudesonide betterbetter

Effect of Budesonide and Prednisolone Enemaon Mean Morning Plasma-Cortisol Levels

Effect of Budesonide and Prednisolone Enemaon Mean Morning Plasma-Cortisol Levels

LofbergLofberg: Aliment Pharmacol : Aliment Pharmacol TherTher, 1994, 1994 CP985036-4

0

100

200

300

400

500

PlasmaPlasmacortisolcortisol((nmolnmol/L)/L)

Treatment duration (weeks)Treatment duration (weeks)

BudesonideBudesonide

0 2 4 6 8

PrednisolonePrednisolone

Oral Cortisone: Mild-to-Severe Active Ulcerative Colitis: Clinical Response and Remission at 6 Weeks

Oral Cortisone: Mild-to-Severe Active Ulcerative Colitis: Clinical Response and Remission at 6 Weeks

16

41 41

69

0

10

20

30

40

50

60

70

80

Clinical response Clinical remission

Perc

ent o

f Pat

ient

sPlacebo (n=101) Cortisone (n=109)

*Clinical remission defined as 1 or 2 stools/day without blood†Clinical response defined as improved or clinical remission Truelove SC. Br Med J. 1954;4884:375.

P<0.001

P<0.001

*†

Oral Cortisone: Mild-to-Severe Active Ulcerative Colitis: Mucosal Healing at 6 Weeks

Oral Cortisone: Mild-to-Severe Active Ulcerative Colitis: Mucosal Healing at 6 Weeks

11

30

0

5

10

15

20

25

30

35

Mucosal healing

Perc

ent o

f Pat

ient

sPlacebo (n=57) Cortisone 100 mg/d (n=63)

*Defined as normal or near normal (slight hyperemia or granularity) mucosaTruelove SC. Br Med J. 1954;4884:375.

P=.02

*

Prednisolone: Mild-to-Severe Active Ulcerative Colitis

Prednisolone: Mild-to-Severe Active Ulcerative Colitis

77 74

01020304050607080

Improvement

Prednisolone 10 mg qidPrednisolone 40 mg q day

23

13

0

10

20

30

40

50

Remission

Prednisolone 10 mg qidPrednisolone 40 mg q day

†Defined as a decrease in the Powell-Tuck index score ≥ 2 points*Defined as a Powell-Tuck index score of 0

† *P

erce

nt o

f pat

ient

s

Per

cent

of p

atie

nts

Powell-Tuck. Scand J Gastroenterol 1978;13:833.

Corticosteroid Maintenance TherapyCorticosteroid Maintenance Therapy

Study Indication Steroid Response (%)Dose Steroid Placebo

Lennard- Maintenance Prednisone 40 40Jones 15 mg

Lennard-Jones et al. Lancet. 1965.

IV Prednisolone 60 mg in Severely Active UC: Clinical Response

IV Prednisolone 60 mg in Severely Active UC: Clinical Response

73

0

10

20

30

40

50

60

70

80

Clinical Response

Clinical response defined as improved or clinical remission

Truelove. Lancet. 1974

†

Pat

ient

s (%

)

Mortality from a severe attack of Ulcerative Colitis

Corticosteroids introduced in 1952

Immediate and Prolonged Outcomes of Corticosteroid Therapy* in UC

Immediate and Prolonged Outcomes of Corticosteroid Therapy* in UC

None 16%

(n=10)

Complete 54%

(n=34)

Partial30%

(n=19)30-DayResponses(n=63)

1-YearResponses(n=63)

Steroid Dependent

22%(n=14)

Prolonged Response

49%(n=31)

Faubion. Gastroenterology. 2001.

Surgery29%

(n=18)

Summers RW, et al. Summers RW, et al. GastroenterologyGastroenterology. 1979;77:847. 1979;77:847--869.869.

Patie

nts

in R

emis

sion

(%)

Patie

nts

in R

emis

sion

(%)

Weeks After RandomizationWeeks After Randomization

7070

6060

5050

4040

3030

2020

1010

0000 55 1010 1515

PrednisonePrednisoneCDAI <150: 0.25 mg/kg (17.5 mg/70 kg)CDAI <150: 0.25 mg/kg (17.5 mg/70 kg)CDAI 150CDAI 150--300: 0.5 mg/kg (35 mg/70 kg300: 0.5 mg/kg (35 mg/70 kgCDAI >300: 0.75 mg/kg (52.5 mg/70 kg)CDAI >300: 0.75 mg/kg (52.5 mg/70 kg)PlaceboPlacebo

60% vs 30%60% vs 30%PP<0.0001<0.0001

Prednisone For Induction of RemissionPrednisone For Induction of Remission

Prednisone Therapy For Maintenance of Remission

Prednisone Therapy For Maintenance of Remission

Patie

nts

(%)

Patie

nts

(%)

Months After RandomizationMonths After RandomizationSummers RW, et al. Summers RW, et al. GastroenterologyGastroenterology. 1979;77:847. 1979;77:847--869.869.

Prednisone 1/4 mg/kg (20 mg)Prednisone 1/4 mg/kg (20 mg)PlaceboPlacebo

100100

9090

8080

7070

6060

5050

0066 1212 1818 2424

Immediate and Prolonged Outcomes of Corticosteroid Therapy in Crohn’s Disease

Immediate and Prolonged Outcomes of Corticosteroid Therapy in Crohn’s Disease

None 16% (n=12)

Complete 58%(n=43)

Partial26%(n=19)

30-DayResponses(n=74)

1-YearResponses(n=74)*

Steroid dependent

32%(n=24)

Prolonged response

28%(n=21)

Faubion WA Jr., et al. Gastroenterology. 2001;121:255-260.

Surgery38%(n=28)

*One patient lost to follow*One patient lost to follow--upup

Budesonide for Active Crohn’s DiseaseBudesonide for Active Crohn’s Disease

11 10

3328

17

25

3642

21

33

51

43

0

10

20

30

40

50

602 wk4 wk8 wk

Patie

nts

in R

emis

sion

(%)

Patie

nts

in R

emis

sion

(%)

n = 66n = 66PlaceboPlacebo

3 mg3 mgn = 67n = 67

9 mg9 mgn = 61n = 61

BudesonideBudesonide

15 mg15 mgn = 64n = 64

Greenberg GR, et al. N Engl J Med. 1994;331:836-841.

P=0.13P=0.13

P<0.001P<0.001P<0.009P<0.009

Budesonide 9 mg vs Prednisolone 40 mg for Active Crohn’s DiseaseBudesonide 9 mg vs Prednisolone 40 mg for Active Crohn’s Disease

PrednisolonePrednisoloneBudesonideBudesonide

Rutgeerts P, et al. N Engl J Med. 1994;331:842-845.

Patie

nts

in R

emis

sion

(%)

Patie

nts

in R

emis

sion

(%)

Weeks of TreatmentWeeks of Treatment

100100

8080

6060

4040

2020

0022 44 66 88 1010

P=0.22P=0.22 P<0.001P<0.001

P=0.12P=0.12 P=0.12P=0.12

Budesonide 9 mg/day versus Mesalamine 4 g/day for Active Crohn’s Disease

Budesonide 9 mg/day versus Mesalamine 4 g/day for Active Crohn’s Disease

Thomsen OO, et al. N Engl J Med. 1998;339:370-374.

Patie

nts

in R

emis

sion

(%)

Patie

nts

in R

emis

sion

(%)

Weeks of TreatmentWeeks of Treatment

BudesonideBudesonideMesalamineMesalamine

100100

8080

6060

4040

2020

0022 44 88 1212 1616

** ††‡‡

*p=0.001; †p=0.004; ‡p<0.001.

Cum

ulat

ive

Prob

abili

tyC

umul

ativ

e Pr

obab

ility

of R

emis

sion

of R

emis

sion

Greenberg GR, et al. Gastroenterology. 1996;110:45-51.DaysDays

1.01.0

0.80.8

0.60.6

0.40.4

0.20.2

0.00.000 5050 100100 150150 200200 250250 300300 350350

Budesonide for Crohn’s Disease: Remission Maintenance

Budesonide for Crohn’s Disease: Remission Maintenance

6 mg Budesonide6 mg Budesonide3 mg Budesonide3 mg BudesonidePlaceboPlacebo

A Pooled Analysis of 4 Placebo-Controlled Trials of Budesonide Maintenance Treatment in Crohn’s Disease: Time to Relapse

A Pooled Analysis of 4 Placebo-Controlled Trials of Budesonide Maintenance Treatment in Crohn’s Disease: Time to Relapse

268 days

170 days156 days

0

100

200

300

Placebo 3 mg BUD 6 mg BUD

Med

ian

Tim

e to

Rel

apse

(Day

s)

Sandborn WJ. Am J Gastroentero 2005;100:1780-7.

P=.28 P=.058P=.0024 placebo vs 6 mg budesonide

P=.0072 across all 3 treatments

BUD = budesonide

A Pooled Analysis of 4 Placebo-Controlled Trials of Budesonide Maintenance Treatment in Crohn’s Disease:

Time to Relapse (cont’d)

A Pooled Analysis of 4 Placebo-Controlled Trials of Budesonide Maintenance Treatment in Crohn’s Disease:

Time to Relapse (cont’d)

Sandborn WJ. Am J Gastroenterol 2005;100:1780-7.

4050

59

3951

6451

37*25*

0

20

40

60

80

100

3 Months 6 Months 12 Months

PlaceboBudesonide 3 mgBudesonide 6 mg

Pro

porti

on o

f Pat

ient

s R

elap

sing

*P<.05

0 20 40 60 80 100 120 140 160Number of Days in Study

Frac

tion

of P

atie

nts

in R

emis

sion

Budesonide >160 days

Placebo 75 days P<.001

0.20.30.40.50.60.70.80.91.01.1

Budesonide 6 mg vs Placebo in Steroid-Dependent Crohn’s Disease

Budesonide 6 mg vs Placebo in Steroid-Dependent Crohn’s Disease

Cortot A, et al. Gut. 2001;48:186–190.

Budesonide 6 mg Versus Mesalamine 3 g in Steroid-Dependent Crohn’s Disease

Budesonide 6 mg Versus Mesalamine 3 g in Steroid-Dependent Crohn’s Disease

(log-rank test, 8.6; P < 0.005).log-rank test, 8.6; P < 0.005

Mantzaris GJ, et al. Clin Gastroenterol Hepatol 2003;1:122-128.

Months

Bone Mineral Density In Relation To Budesonide And Prednisolone

-1.3-1.2-1.1

-1-0.9-0.8-0.7-0.6-0.5-0.4-0.3

0 6 12 18 24

BudesonidePrednisolone

Steroid Naive

Previous Steroid Treatment

Steroid Dependent

Schoon EJ, et al. Clin Gastroenterol Hepatol 2005;3:113-121.

Bon

e D

ensi

ty (T

Bon

e D

ensi

ty (T

-- Sco

res)

Scor

es)

Corticosteroid ToxicityCorticosteroid Toxicity

• Moon face

• Acne

• Ecchymoses

• Hypertension

• Hirsutism

• Petechial bleeding

• Striae

• Diabetes• Infection• Osteonecrosis• Osteoporosis• Myopathy• Cataracts• Glaucoma• Psychosis

Infections and mortality in the TREAT registry: 15,000 patient-years of experience

Infections and mortality in the TREAT registry: 15,000 patient-years of experience

Lichenstein GR, et al. Gastroenterology 2006;130(suppl 4):A-71Lichtenstein GR, et al. Clin Gastroenterol Hepatol 2006;4:621–630

Multivariate analysis

*p=0.001 **p<0.00010

0.5

1

1.5

2

2.5

3

3.5

4

4.5

IFX

Odd

s ra

tio

Mortality Serious infections

AZA6-MPMTX

Steroids

** IFX AZA6-MPMTX

Steroids

****

IFX = infliximab; AZA = azathioprine; MTX = methotrexate

Side Effects of CIR Budesonide and Prednisolonein Patients With Active Crohn’s Disease

Side Effects of CIR Budesonide and Prednisolonein Patients With Active Crohn’s Disease

Side Effect Budesonide Prednisolone

Moon face 17% 35%

Acne 6% 23%

Swollen ankles 2% 11%

Easy bruising 2% 7%

Hirsutism 2% 2%

Buffalo hump 1% 3%

Skin striae 0% 0%

Other 9% 16%

Total 40% 98%Rutgeerts. N Engl J Med 1994.

ConclusionsConclusions• Conventional steroids and budesonide are highly

effective as induction agents in patients with ulcerative colitis and Crohn’s disease

• These agents are not effective as maintenance therapy

• Steroid dependence is frequent

• Serious toxicity is associated with conventional steroids including an increased risk of mortality

• The use of conventional steroids is likely to decrease in future years

• Oral budesonide has significantly less steroid side effects than conventional steroids