1. Vanderbilt University Medical Centre
Updates on steroids and 5-ASA use: What the clinician needs to know in 2014
David A Schwartz, M.D.
Professor Medicine
Director IBD Center
Vanderbilt University Medical Centre
Nashville, TN

2. Updates on steroids and 5-ASA use: What the clinician needs to know in 2014
i.e. - Say Hello to Some Old Friends
David A Schwartz, M.D.
Professor Medicine
Director IBD Center
Vanderbilt University Medical Centre
Nashville, TN

3. Relevant Disclosures
I have served as a consultant for:
Santarus

4. Patient
25 yo male comes to office with 8 week history of abdominal pain and diarrhea (4x / day) with urgency
He has had UC (pancolitis) for 3 years. Required course of prednisone with initial presentation.
Since has done well on 2.4 grams of 5-asa
Current symptoms began after course of antibiotics for URI. C.diff has been checked multiple times and has been negative.

5. Patient (Part B)
On exam he looks well, afebrile. No tenderness to palpation of abdomen
Labs: normal with exception of Crp mildly elevated at 15
Stool studies negative
Colonoscopy shows ulcerations, friability, and muco - purulence involving the whole colon. The ileum is normal.

6. Patient (Part B)
On exam he looks well, afebrile. No tenderness to palpation of abdomen
Labs: normal with exception of Crp mildly elevated at 15
Stool studies negative
Colonoscopy shows ulcerations, friability, and muco - purulence involving the whole colon. The ileum is normal.
What to do now?
Is more 5-asa better
Dual therapy?
Budesonide (colonic)
Steroids

7. Sequential Therapies for UC
Disease Severity
at Presentation
Colectomy
Anti-TNF
Vedolizumab
Cyclosporine
Anti-TNF/Vedolizumab
Thiopurine
Severe
Moderate
Mild
Aminosalicylate/
Thiopurine
Corticosteroid
Aminosalicylate
Aminosalicylate
Induction
Maintenance
Therapy is stepped up according to severity at presentation or failure at prior step

8. Sequential Therapies for UC
Disease Severity
at Presentation
Colectomy
Anti-TNF
Vedolizumab
Cyclosporine
Anti-TNF/Vedolizumab
Thiopurine
Severe
Moderate
Mild
Aminosalicylate/
Thiopurine
Corticosteroid
Budesonide?
Aminosalicylate
Aminosalicylate
Induction
Maintenance
Therapy is stepped up according to severity at presentation or failure at prior step

9. Aminosalicylates

10. 5-ASA and Steroids as Index Therapies in Newly Diagnosed IBD
Retrospective analysis of MarketScan Database
Employer and health plan sourced medical and pharmacy claims data on >30 million insured US patients
Data analyzed from 2006 through 2010
Monotherapy only allowed
UC1: n=19,878
5-ASA used as first therapy: 69%
Corticosteroids used as first therapy: 27%
CD1: n=13,005
5-ASA used as first therapy: 47%
Corticosteroids used as first therapy: 40%
1. Rubin DT, et al. Alim Pharm, 2014

11. Oral 5-ASA Formulations
Sites of Delivery
Colon
Terminal Ileum
Colon
(release at pH  7)
Terminal Ileum
Colon
(release at pH  6)
Duodenum Ileum
Colon
Sulfasalazine
Olsalazine
Balsalazide
Delayed release mesalamine
MMX mesalamine
Granulated mesalamine
Controlled release mesalamine
Baumgart DC, Sandborn WJ. Lancet. 2007;369:
Sandborn WJ. J Clin Gastroenterol. 2008;42:

12. Advantages of 5-ASA for Mild to Moderate UC
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Advantages of 5-ASA for Mild to Moderate UC
Efficacy for induction of response is: % to 70%
Efficacy for induction of remission is % to 40%
Excellent safety profile
Hanauer SB et al. Ann Intern Med. 1996;124:204.
Hanauer SB et al. Am J Gastroenterol. 1993;88:1188.
Hanauer SB et al. Am J Gastroenterol. 2005;100:2478.
Levine DS et al. Am J Gastroenterol. 2002;97:1398.
Sninsky CA et al. Ann Intern Med. 1991;115:350.

13. Meta-Analysis of Mesalamine (4g/day) in Active Crohn’s Disease
Mesalamine 4 g minus Placebo
Mesalamine 4 g
Placebo
-10
-10
P=0.7
P=0.7
P=0.05
P=0.5
-20
-20
-30
P=0.04
P=0.04
-30
Change from baseline in CDAI score
-40
P=0.7
-50
P=0.7
-40
-60
-50
-70
P=0.04
P=0.005
P=0.005
P=0.005
P=0.005
P=0.05
P=0.05
P=0.04
-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, Clinical Gastroenterology & Hepatology 2004

14. Meta-Analysis of Mesalamine (4g/day) in Active Crohn’s Disease
Mesalamine 4 g minus Placebo
Mesalamine 4 g
Placebo
-10
-10
P=0.7
P=0.7
P=0.05
P=0.5
-20
-20
-30
P=0.04
P=0.04
-30
Change from baseline in CDAI score
-40
P=0.7
-50
P=0.7
-40
-60
-50
-70
P=0.04
P=0.005
P=0.005
P=0.005
P=0.005
P=0.05
P=0.05
P=0.04
-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, Clinical Gastroenterology & Hepatology 2004

15. Meta-Analysis of Mesalamine (4g/day) in Active Crohn’s Disease
Mesalamine 4 g minus Placebo
Mesalamine 4 g
Placebo
-10
-10
P=0.7
P=0.7
P=0.05
P=0.5
-20
-20
-30
P=0.04
P=0.04
-30
Change from baseline in CDAI score
-40
P=0.7
-50
P=0.7
-40
Clinically meaningless
-60
-50
-70
P=0.04
P=0.005
P=0.005
P=0.005
P=0.005
P=0.05
P=0.05
P=0.04
-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, Clinical Gastroenterology & Hepatology 2004

16. Mesalamine Maintenance of Remission in Crohn’s Disease
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Mesalamine Maintenance of Remission in Crohn’s Disease
Study
Year
Pts (n)
Caprilli
1994 95
McLeod
1995
163
Brignola
1995 87
Sutherland
1997 66
Overall
411
Thomson
1990
248
Prantera
1992
125
Brignola
1992 44
Gendre
1993
161
Bresci
1994 66
Thomson
1995
286
Arber
1995 59
Modigliani
1996 85
Sutherland
1997
180
De Franchis
1997
117
Overall
1,371
-0.5
-0.4
-0.3
-0.2
-0.1
0.0
0.1
0.2
0.3
0.4
0.5
NNT~20
Favors Treatment
Favors Control
Risk Difference 95% CI
Cammà C et al. Gastroenterology. 1997;113:1465.

17. Mesalamine Maintenance of Remission in Crohn’s Disease
Curatio PowerPoint Template
11/12/2018 9:47 PM
Mesalamine Maintenance of Remission in Crohn’s Disease
Study
Year
Pts (n)
Caprilli
1994 95
McLeod
1995
163
Brignola
1995 87
Sutherland
1997 66
Overall
411
Thomson
1990
248
Prantera
1992
125
Brignola
1992 44
Gendre
1993
161
Bresci
1994 66
Thomson
1995
286
Arber
1995 59
Modigliani
1996 85
Sutherland
1997
180
De Franchis
1997
117
Overall
1,371
-0.5
-0.4
-0.3
-0.2
-0.1
0.0
0.1
0.2
0.3
0.4
0.5
NNT~20
Favors Treatment
Favors Control
Risk Difference 95% CI
Cammà C et al. Gastroenterology. 1997;113:1465.

18. Is more 5-ASA Better?

19. Patients in Clinical and Endoscopic Delayed-Release Mesalamine†
Dose Response at Week 8: Delayed-Release Mesalamine in Mild to Moderate UC
100
Kamm et al1 Lichtenstein et al2 90 80 70 60
P=0.01*
P=0.007*
Remission at Week 8 (%)
Patients in Clinical and Endoscopic 50
P<0.001* 41 41
P=0.009* 40 34 29 30 22 20 13 10
Placebo
2.4 g/day
4.8 g/day
Delayed-Release Mesalamine†
*P values represent active treatment vs placebo †delayed release mesalamine
1. Kamm MA et al. Gastroenterology. 2007;132: Lichtenstein GR et al. Clin Gastroenterol Hepatol.2007;5:95.

20. Dose Response at Week 6: Delayed-Release Mesalamine
ASCEND II1
ASCEND III2
Mild UC (n=110)
Moderate UC (n=772)
Moderate UC (n=254)
100
100 90
P<0.05 90
P=NS 80 72 80
P<0.05 70 66 70 70 59 60 60
P=NS
Patients With Treatment
Success at Week 6 (%)
Patients With Treatment
Success at Week 6 (%) 50
P=NS 40 50 33 40 40 30 30 20 20 10 10
2.4 g/day
4.8 g/day
2.4 g/day
4.8 g/day
Delayed-Release Mesalamine*
Delayed-Release Mesalamine*
1. Hanauer SB et al. Am J Gastroenterol. 2005;100: Sandborn WJ et al. Gastroenterology. 2009;137:1934.

21. History of More-Difficult-to-Treat Disease Predicts Response to Higher Dose Delayed-Release Mesalamine for Moderate UC
Treatment success at week 6 in patients having taken previous UC therapy
2.4 g/day (800 mg tabs) 80
4.8 g/day (800 mg tabs)
70%
70%
70% 60
64%
64%
61%
58%
54%
Patients (%) 40 20
n=323
n=338
n=188
n=192
n=157
n=157
n=234
n=230 *
Oral 5-ASA P=0.07
Rectal Therapies P=0.06
Steroids P=0.05
≥2 Medications *P=0.01
*Included oral 5-ASAs, rectal therapies, steroids, or immunomodulators
Sandborn WJ et al. Gastroenterology. 2009;137:1934.

22. Adverse Effects Associated With Oral 5-ASAs
FDA recommends monitoring BUN/serum creatinine
Kornbluth A, Sachar DB. Am J Gastroenterol. 2010;105:501.
Sands B. Gastroenterology. 2000;118:S68.
Azulfidine (sulfasalazine) [package insert]. New York, NY: Pfizer; August 2006.

23. Adverse Effects Associated With Oral 5-ASAs
Headache
Nausea/vomiting
Dyspepsia
Anorexia
Rash
Bone marrow suppression
Interstitial nephritis
Megaloblastic anemia
Apparently reversible oligospermia
Folate malabsorption
Connective tissue disease
Sulfasalazine
Pancreatitis
Pericarditis
Hepatitis
Paradoxical exacerbation of colitis
FDA recommends monitoring BUN/serum creatinine
Kornbluth A, Sachar DB. Am J Gastroenterol. 2010;105:501.
Sands B. Gastroenterology. 2000;118:S68.
Azulfidine (sulfasalazine) [package insert]. New York, NY: Pfizer; August 2006.

24. Adverse Effects Associated With Oral 5-ASAs
Headache
Nausea/vomiting
Dyspepsia
Anorexia
Rash
Bone marrow suppression
Interstitial nephritis
Megaloblastic anemia
Apparently reversible oligospermia
Folate malabsorption
Connective tissue disease
Sulfasalazine
Pancreatitis
Pericarditis
Hepatitis
Paradoxical exacerbation of colitis
Olsalazine, Balsalazide,
Mesalamine
Headache
Nausea
Rash
Hair loss
Interstitial nephritis
Pericarditis
Pneumonitis
Hepatitis
Pancreatitis
Paradoxical exacerbation of colitis
Secretory diarrhea (olsalazine)
FDA recommends monitoring BUN/serum creatinine
Kornbluth A, Sachar DB. Am J Gastroenterol. 2010;105:501.
Sands B. Gastroenterology. 2000;118:S68.
Azulfidine (sulfasalazine) [package insert]. New York, NY: Pfizer; August 2006.

25. Do We Need To Maintain 5-ASA at the Same Dose We Use to Induce Remission?

26. Maintenance Efficacy of Mesalamine: Patients in Remission at 6 Months70
P=0.036 60 50
Patients in Remission
at 6 Months (%) 40 30 20 10
Placebo
(n=63)
0.8 g/day
(n=68)
1.6 g/day
(n=58)
Delayed-Release
Mesalamine*
Hanauer SB et al. Ann Intern Med. 1996;124:204.

27. Maintenance Efficacy of Mesalamine: Patients in Remission at 6 Months70
P=0.036 60 50
Patients in Remission
at 6 Months (%) 40
40% 30 20 10
Placebo
(n=63)
0.8 g/day
(n=68)
1.6 g/day
(n=58)
Delayed-Release
Mesalamine*
Hanauer SB et al. Ann Intern Med. 1996;124:204.

28. Maintenance Efficacy of Mesalamine: Patients in Remission at 6 Months70
P=0.036 60
59% 50
Patients in Remission
at 6 Months (%) 40
40% 30 20 10
Placebo
(n=63)
0.8 g/day
(n=68)
1.6 g/day
(n=58)
Delayed-Release
Mesalamine*
Hanauer SB et al. Ann Intern Med. 1996;124:204.

29. Maintenance Efficacy of Mesalamine: Patients in Remission at 6 Months70
P=0.036
66% 60
59% 50
Patients in Remission
at 6 Months (%) 40
40% 30 20 10
Placebo
(n=63)
0.8 g/day
(n=68)
1.6 g/day
(n=58)
Delayed-Release
Mesalamine*
Hanauer SB et al. Ann Intern Med. 1996;124:204.

30. Normal at Final Data Capture (%)
Maintenance of Remission Is More Successful When Maintenance Dose = Induction Dose
Maintenance dose < Induction dose
Maintenance dose = Induction dose 90
78.6 80 70
65.9 60
53.3
Final mesalamine induction dose
≤2.4 g/day or –4.0 g/day or ≥4.8 g/day
51.2
Normal at Final Data Capture (%) 50 40 30 20 10
N=43
N=135
N=60
N=173
Mild UC
Moderate or Severe UC
Sandborn WJ et al. Am J Gastroenterol. 2005;100:S312. Abstract 846.

31. Does Mode of Delivery Matter Or Is Dose More Important?

32. Treatment of Distal UC: Benefits of Rectal Mesalamine Therapy
100
Oral (2.4 g/d) *
Rectal (4 g/d)
Combined 75 * *
Patients Reporting No Rectal Bleeding (%) 50 25
1 Week
2 Weeks
3 Weeks
6 Weeks
*P<0.05 vs oral alone
Safdi M et al. Am J Gastroenterol. 1997;92:1867.

33. Benefits of Combination Rectal and Oral Mesalamine for Extensive Mild/Moderate UC
Mesalamine* 4 g total PO (in divided doses; 2 g BID) + mesalamine enema 1 g HS (N=71)
Mesalamine 4 g total PO (in divided doses; 2 g BID) + placebo enema HS (N=56)
P=0.0008
100 89 90 80 70 62 60
P=NS
No. of Patients (%) 50 44 40 34 30 20 10
Remission
Improvement
Week 4
*Controlled-release mesalamine
Marteau P et al. Gut. 2005;54:960.

34. Aminosalicylates Heal the Bowel
If Given Time to Work

35. Mucosal Healing in ASCEND I and II
Mucosal Healing at Weeks 3 and 6
* p< 0.05 between 2.4 g/day and 4.8 g/day at week 6 90 80
70 60 50 40 30 20 10 * 80 68 65 58
% Patients with Mucosal Healing
2.4 g/day
4.8 g/day
n = n = 156
Week 3
n = n = 153
Week 6
Lichtenstein GR, et al. Aliment Pharmacol Ther. 2011;33:672–678.

36. Mucosal Healing Analysis
Endoscopy subscore of 0
P=0.125
n=169
n=153
Analysis includes patients with endoscopy subscore of ≥ 2 at baseline
Lichtenstein GR, et al. Aliment Pharmacol Ther doi: /j x

37. Endoscopic Remission at 6 Mns with MMX mesalamine
D’Haens et al. Am J Gastro 2012

38. 5-ASA and Chemoprevention: Is It Real?

39. 5-ASA and Development of Cancer or Dysplasia - 2005
Velayos et al, Am j Gastro 2005

40. 5-ASA and Development of Cancer or Dysplasia - 2012
Nguyen et al, Am j Gastro 2012

41. Steroids

42. Steroids Were A Revolutionary Treatment in IBD!
Mortality from a severe attack of ulcerative colitis Corticosteroids introduced in 1952 40 30
Mortality (%) 20 10
1938– 1952
1953– 1962
1963– 1972
1973– 1982
1983–
1987

43. Corticosteroids: Onset of Action
N = 58 outpatients with active UC (60 courses of treatment in 58 patients)
Double blind, non-placebo controlled trial
Treatment arms: Prednisone 20, 40 and 60 mg
N=20 in each arm
No. of Patients in Remission
60 mg daily
n=20
40 mg daily
20 mg daily
Weeks 15 10 5
END
POINTS:
Remission
Improved
No 
Worse*
20 mg 6 3 5
40 mg 13 1
60 mg
*based upon symptoms
Start
Remission = “No Symptoms; Inactive or Normal Mucosa”
Baron JH, et al. Br Med J. 1962;2(5302):

44. Corticosteroids: Short- and Long-Term Efficacy for IBDUC CD
Faubion WA, Jr. et al. Gastroenterology. 2001;121:255

45. Corticosteroid Toxicity
Moon face
Acne
Ecchymoses
Hypertension
Hirsutism
Petechial bleeding
Striae
Diabetes
Infection
Osteonecrosis
Osteoporosis
Myopathy
Cataracts
Glaucoma
Psychosis
needs touch up on graphics.

46. Minimizing Steroid Toxicity
Assess for risk factors for osteoporosis and perform DEXA if appropriate
Supplement Vit D, calcium daily
1200 mg Calcium
800 IU vitamin D
Monitor for symptoms of elevated glucose
Have an exit strategy for steroid use
Kane S. Curr Gastroenterol Rep. 2010;12(6):502-6.

47. Budesonide for UC and CD

48. Oral forms of budesonide
Controlled ileal-release (CIR): Entocort® EC1
Enteric-coated granules that release at pH >5.5
Majority absorbed in ileum and cecum (69%, 95% CI: 50–84%)
Indication: Treatment of acute mild-to-moderate CD, involving ileum and / or ascending colon, maintenance of clinical remission for up to 3 months
pH-modified release: Budenofalk®1
Dissolves at pH >6.4
Maximal release in distal small intestine
Not approved in US
Extended release tablets: Budesonide MMX®
Releases budesonide throughout colon2
Enteric coat dissolves at pH 7
Proposed indication: Induction of remission of active mild-to-moderate UC in adults
1Gross, Expert Opin Pharmacother 2008; 9: 1257–65
2Brunner et al, Br J Clin Pharmacol 2006; 61: 31–38

49. Remission Rates in Acute Crohn’s: Studies With Budesonide CIR
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Remission Rates in Acute Crohn’s: Studies With Budesonide CIR 70 60
*NS vs placebo 50 40
Remission Rates at
8 Weeks (%) 30 20 10
Bud CIR 9 mg QD
Bud CIR 4.5 mg BID*
Placebo BID
Mesalamine 2g BID
Prednisolone 40 mg
Campieri M et al. Gut. 1997;41:209.
Greenberg G et al. N Engl J Med. 1994;331:836.
Rutgeerts P et al. N Engl J Med. 1994;331:842.
Thomsen O et al. Am J Gastroenterol. 2002;97:649.

50. Oral Budesonide: Efficacy as Maintenance Therapy
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Oral Budesonide: Efficacy as Maintenance Therapy
1.0
Budesonide 6 mg
0.9
Budesonide 3 mg
0.8
Placebo
0.7
0.6
Cumulative Probability of Remission
0.5
0.4
0.3
0.2
0.1
0.0
100
Time (Days)
200
300
Greenberg GR et al. Gastroenterology. 1996;110:45.

51. CORE I and II: Budesonide MMX Primary Endpoint: Combined Clinical and Endoscopic Remission*
*p =
**p =
***p = **
***
% of Patients
N=121
N=89
N=210
N=123
N=109
N=232
N=121
N=109
N=230
N=124
N=103
Mes= Mesalamine
Bud = Budesonide
B-MMX= Budesonide MMX
Sandborn WJ, et al. Gastroenterology Nov;143(5):
Travis SP, et al. Gut Feb 22.

52. Clinical and Endoscopic Remission
CORE I and II: Budesonide MMX Remission and Mucosal Healing: Stratified by Disease Extent
(up to the splenic flexure)
(beyond the splenic flexure)
% Subjects
N= 41
N= 34
N= 40
N= 34
N= 32
N= 56
N= 41
N= 34
N= 40
N= 34
N= 32
N= 56
Clinical and Endoscopic Remission
Mucosal Healing
*p =
Sandborn WJ, et al. Gastroenterology Nov;143(5):
Travis SP, et al. Gut Feb 22.

53. CORE I and II Trials
Pooled Safety Data Analysis: Potential Glucocorticoid Effects
Glucocorticoid
Effects
Placebo
N=258
N (%)
MMX 9 mg
N=255
MMX 6 mg
N=254
Mesalamine
N=127
Budesonide
N=126
TOTAL
N=1020
Overall
27 (10.5)
26 (10.2)
19 (7.5)
15 (11.8)
17 (13.5)
104 (10.2)
Moon face
4 (1.6)
3 (1.2)
2 (1.6)
14 (1.4)
Striae rubrae
2 (0.8)
2 (0.2)
Flushing
1 (0.4)
1 (0.8)
7 (0.7)
Fluid retention
3 (2.4)
11 (1.1)
Mood changes
11 (4.3)
9 (3.5)
10 (3.9)
6 (4.8)
39 (3.8)
Sleep changes
12 (4.7)
7 (2.7)
9 (7.1)
Insomnia
8 (3.1)
6 (2.4)
5 (4.0)
27 (2.6)
Acne
5 (1.9)
6 (4.7)
22 (2.2)
Hirsutism
3 (0.3)
Sandborn WJ, et al. Gastroenterology
Travis SP, et al. Gut Feb 22.

54. Patient Update Patient 5-ASA dose increased to 4.8 grams / day
Seen back in clinic and better but with some mild residual symptoms
rectal therapy added nightly
Symptoms resolve

55. Summary: Old Drugs, New Ideas
5-ASA
Maximize delivery of 5-ASA (by adjusting delivery system and dose)
Watch for the rare intolerance, monitor kidneys
Longer term use does achieve more healing
Chemoprevention probably of little benefit
Steroids
Short-term provide excellent response
Newer options and “organ specific” delivery is effective and has less toxicity

56. Thank you for your time!