State of the Art Management
of Crohn’s Disease
Talal Al-Taweel
Haya Al-Habeeb Gastroenterology Center
Mubarak Al-Kabeer Hospital
March 2015
S
Disclosures
S Travel/accommodation/meeting expenses: Janssen;
AbbVie; Novartis
Introduction
S
Definition
 Crohn's disease is a condition of chronic
inflammation potentially involving any location of
the alimentary tract from mouth to anus, but with a
propensity for the distal small bowel and proximal
large bowel.
 Inflammation is discontinuous along the longitudinal
axis of the intestine and can involve all layers from
mucosa to serosa
History

Intestinal inflammation characteristic of Crohn's disease first
described by Morgagni in 1761

In 1932, the landmark publication of Crohn, Ginzburg, and
Oppenheimer called attention to “terminal ileitis” as a distinct entity
and chronic disease

Underwent many naming changes due to discovery of multiple GI
tract sites

“Crohn’s disease” has been adopted to encompass the many clinical
presentations of this pathologic entity
General Approach
S
Step Up or Top Down?
 Step up: Begin treatment with drugs that have a relatively
long track record and safety profile progressing to more
potent (and potentially more toxic) treatments in patients
with severe or refractory disease
 Top down: Aggressive treatment with more potent
treatments (such as infliximab or other
immunomodulators) relatively early in the course of
disease, before patients become corticosteroid dependent
and possibly even before they receive corticosteroids
D’Haens et al. Lancet 2008
Weighing down the Value of TopDown Therapy
Pros
 Early promotion of
mucosal healing to
prevent complications
 Evidence of
immunomodulators
and biologics to
promote mucosal
healing
Cons
 Serious side effects
 Development of
antibodies (biologics)
 Cost
 Majority of patients do
not require more potent
treatments initially
So why not go all guns a blazing?
 Not every patient needs “top-down” or “early
intensive therapy”
 We need to determine
 Who has high risk versus low risk disease
 How patients may respond to specific
medications
 If patients agree with our plan
Not everyone develops complications of
Not everyone
develops complications
Crohn’s
disease quickly
of CD quickly
100
Cumulative Probability (%)
90
80
70
60
2 years
5 years
Penetrating
50
40
30
Stricturing
20
10
Inflammatory
0
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240
Months
N=
Cosnes et al. Inflamm Bowel Dis 2002
Who is going to have “bad”
Crohn’s?
Clinical Risk Factor
Age of onset < 40 years
Perianal lesion at diagnosis
Required steroids for first flare
Smokers
P value
0.0004
0.01
0.0001
0.09
Beaugerie et al. Gastroenterology 2006
How about “good” Crohn’s?
Cosnes et al. Gut 2012
Drugs
S
Sulfasalazine
 5-ASA linked to sulfapyridine by an azo bond
 Salicylazosulfapyridine (sulfasalazine) was
originally proposed as a treatment for
rheumatoid arthritis
 Subsequently discovered that sulfasalazine was
also efficacious in treating IBD.
Sulfasalazine
 Large controlled clinical trials completed in the 1970s and
the 1980s demonstrated benefits of sulfasalazine 3-6g/day
over placebo for induction of remission with mild to
moderate active ileocolonic and colonic CD
 Not effective for patients with active disease limited to the
small intestine
 No consistent maintenance benefits after medical inductive
therapy
 Use largely limited by side effect profile
5-ASA
 Salicylazosulfapyridine (sulfasalazine) was originally
proposed as a treatment for rheumatoid arthritis
 Subsequently discovered that sulfasalazine was also
efficacious in treating IBD.
 5-aminosalicylic acid (5-ASA) medications were
developed because many patients were intolerant of or
allergic to sulfasalazine
5-ASA
 Conflicting older data of efficacy in CD, with variable
definitions of remission and response
 Meta-analysis of three large trials with mesalamine, 4
g daily, demonstrated a statistically significant (P =
0.04) but a non-clinically relevant difference (CDAI
benefit of 18 points) compared with placebo
 Two more recent meta-analyses in 2010 and 2011
showed mesalamine not to be superior to placebo in
induction or maintenance of remission
Hanauer et al. Clin Gastroenterol Hepatol 2004
Ford et al Am J Gastroenterol 2011
Geary Inflamm Bowel Dis 2007
Antibiotics

Widely used but no consistent evidence for luminal disease

Metronidazole


Not more effective than placebo for inducing remission in mild to
moderate disease

Post hoc subgroup analysis indicated that metronidazole might be
effective in patients with colonic involvement

The well-documented risk of peripheral neuropathy necessitates
monitoring for symptoms or signs of paresthesias
Ciprofloxacin, rifaximin and anti-TB drugs - inconsistent evidence of
efficacy in luminal disease
Sutherland et al. Gut 1991
Antibiotics

Perianal disease

Use well established in fistulizing peri-anal disease

Abscesses require surgical drainage

Non-suppurative perianal complications of CD typically
respond to metronidazole alone or in combination with
ciprofloxacin

No placebo-controlled maintenance trials, but it appears that
continuous therapy is necessary to prevent recurrent drainage
Steroids

2 large major published RCTs show that corticosteroids are
effective agents for induction of remission in patients with CD.

The National Cooperative Crohn’s Disease Study (NCCDS)

Prednisone 0.5– 0.75 mg/kg daily with tapering over 17
weeks

60% clinical remission rates compared with 30% in the
placebo group
Steroids
 European Cooperative Crohn’s Disease Study (ECCDS)
 Prednisolone 1 mg/kg with tapering over 18 weeks
 83% clinical remission vs. 38% receiving placebo
 Preponderance of evidence that low-dose conventional
steroids are ineffective for maintaining remissions in CD
and therefore should not be used as long-term agents to
prevent relapse of CD
IV vs. PO steroids?
 Parenteral steroids are used for severe or fulminant CD
unresponsive to PO steroids
 No studies directly addressing issue, but overwhelming
anecdotal evidence supports its use
 Methylprednisolone (60mg/day) preferred over
hydrocortisone due to its decreased mineralocorticoid
effects
Budesonide
 Budesonide is a corticosteroid with a high
hepatic first pass metabolism
 Predominantly topical glucocorticoid activity
resulting in fewer systemic side effects
compared with conventional steroids
 Best combination of short-term efficacy and
safety in a series of well-controlled
randomized trials.
Greenberg NEJM 1994
Budesonide
 Controlled-release oral budesonide formulations at a dose
of 9mg/day have been demonstrated to be more effective
than mesalamine 4g/day and similar efficacy to steroids
for the treatment of disease in patients with mild–
moderately active CD involving the distal ileum and/or
right colon
 Reduces the time to relapse in ileal and/or right colonic
disease, but does not provide significant maintenance
benefits after 6 months
Seow Expert Opinion on Drug Metabolism and Toxicology 2009
Tromm Gastroenterology 2011
Thiopurines
 Thiopurines should be considered for patients who
 require two or more corticosteroid courses within a calendar
year
 steroid dependent
 steroid refractory
 postoperative prophylaxis of complex (fistulizing or extensive)
CD
 Slow onset of action, with a response usually seen within 3-6
months.
Azathioprine or 6-mercaptopurine for induction of remission in Crohn’s disease (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Thiopurines – induction Rx
S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]
Azathioprine (AZA) or 6-mercaptopurine (6-MP) versus placebo for induction of remission in Crohn’s disease
Patient or population: Patients with active Crohn’s disease
Settings: Outpatients
Intervention: Azathioprine or 6-mercaptopurine versus placebo
Outcomes
Illustrative comparative risks* (95% CI)
Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Assumed risk
Corresponding risk
Control
AZA or 6-MP versus
placebo
372 per 10001
458 per 1000
(361 to 577)
RR 1.23
(0.97 to 1.55)
380
(5 studies)
⊕⊕⊕⃝
Moderate2
Clinical remissionor im- 359 per 10001
provement
452 per 1000
(352 to 582)
RR 1.26
(0.98 to 1.62)
434
(8 studies)
⊕⊕⊕⃝
Moderate3
Fistula improvement or 286 per 10001
healing
572 per 1000
(192 to 1696)
RR 2.00
(0.67 to 5.93)
18
(3 studies)
⊕⊕⃝ ⃝
Low4
457 per 10001
612 per 1000
(466 to 809)
RR 1.34
(1.02 to 1.77)
143
(4 studies)
⊕⊕⊕⃝
Moderate5
Withdrawals due to ad- 53 per 10001
verse events
90 per 1000
(50 to 163)
RR 1.70
(0.94 to 3.08)
510
(8 studies)
⊕⊕⊕⃝
Moderate6
Serious Adverse events 38 per 10001
98 per 1000
(35 to 271)
RR 2.57
(0.92 to 7.13)
216 (2 studies)
⊕⊕⃝ ⃝
Low7
Clinical remission
Steroid sparing effect
Comments
* The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the
assumed risk in the comparison group and the relative effect of the intervention (and its 95%CI).
CI: Confidence interval; RR: Risk ratio
3
Chande et al. Cochrane Database Syst Rev 2013
Outcome: 1 Maintenance
of 1.1.
remission
(Azathioprine)1 Maintenance of remission, Outcome 1 Maintenance of remission (Azathioprine).
Analysis
Comparison
Thiopurines - maintenance Rx
Review: Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn’s disease
Peto
Odds Ratio
Study or subgroup
Treatmentof remission Control
Comparison: 1 Maintenance
n/N
n/N
Weight
Peto,Fixed,95%CI
Outcome: 1 Maintenance of remission (Azathioprine)
Peto
Odds Ratio
Peto,Fixed,95%CI
1 Azathioprine dose 2.5 mg/kg/day
Candy 1995
Study or subgroup
Summers 1979
14/25
16/19
2/20
Treatment
n/N 15/20
1 Azathioprine dose 2.5 mg/kg/day
Subtotal (95% CI )
44
Candy 1995
Peto
Odds Ratio
Control
n/N
11.3 %
Peto ]
7.12 [ 2.11, 23.99
7.1 %
P1.73
eto,Fixed,95%CI
[ 0.37, 8.05 ]
18.3 %
4.13 [ 1.59, 10.71 ]
Weight
Peto,Fixed,95%CI
40
Odds Ratio
14/25
2/20
11.3 %
7.12 [ 2.11, 23.99 ]
16/19
Heterogeneity: Chi2 =Summers
2.00, df1979
= 1 (P = 0.16); I2 =50%
15/20
7.1 %
1.73 [ 0.37, 8.05 ]
40
18.3 %
4.13 [ 1.59, 10.71 ]
Total events: 30 (Treatment), 17 (Control)
Test for overall effect:
Z = 2.92
(P = CI)
0.0035)
Subtotal
(95%
44
Total
30 (Treatment), 17 (Control)
2 Azathioprine dose
2.0events:
mg/kg/day
2
df = 1 (P = 0.16); I29/29
=50%
D’Haens 2007 Heterogeneity: Chi = 2.00,
18/32
16.5 %
2.73 [ 1.00, 7.45 ]
8.8 %
3.17 [ 0.80, 12.54 ]
Test for overall effect: Z = 2.92 (P = 0.0035)
Lemann 2005 2 Azathioprine dose 2.0 mg/kg/day
38/40
D’Haens 2007
O’Donoghue 1978
13/23
Lemann 2005
Rosenberg 1975
Willoughby 1971
O’Donoghue 1978
9/29
8/27
38/40
7/10
4/5
4/10
7/10
110
Total events: 80 (Treatment), 59 (Control)
Subtotal (95% CI)
4/5
16.5 %
2.73 [ 1.00, 7.45 ]
8.8 %
3.17 [ 0.80, 12.54 ]
13.4 %
36/43
5.6 %
13/23
Rosenberg 1975
Subtotal (95% CI
)
Willoughby
1971
36/43
18/32
8/27
2/5
13.4 %
2.9 %
4/10
114
110
Heterogeneity: Chi2 = 0.15, df = 4 (P = 1.00); I2 =0.0%
5.6 %
2/5
47.2 %
2.9 %
114
47.2 %
2.95 [ 0.97, 9.00 ]
3.16 [ 0.57, 17.62 ]
2.95 [ 0.97, 9.00 ]
4.48 [ 0.41, 49.42 ]
3.16 [ 0.57, 17.62 ]
3.014.48
[ 1.66,
5.45
[ 0.41, 49.42
] ]
3.01 [ 1.66, 5.45 ]
Total events: 80 (Treatment), 59 (Control)
Test for overall effect:
Z = 3.64 (P
Heterogeneity:
Chi=2 =0.00027)
0.15, df = 4 (P = 1.00); I2 =0.0%
3 Azathioprine dose
1.0
Test
formg/kg/day
overall effect: Z = 3.64 (P = 0.00027)
Summers 1979 3 Azathioprine dose 1.0 mg/kg/day
37/54
Summers 1979
Subtotal (95% CI )
Subtotal (95% CI)
54
65/101
37/54
54
Total events: 37 (Treatment), 65 (Control)
101
34.5 %
65/101
34.5 %
101
1.20 [ 0.60, 2.41 ]
1.20 [ 0.60, 2.41 ]
34.5 %
1.20 [ 0.60, 2.41 ]
100.0
%%
100.0
2.32
1.55,3.49
3.49
2.32 [[1.55,
] ]
34.5 %
1.20 [ 0.60, 2.41 ]
Total events: 37 (Treatment), 65 (Control)
Heterogeneity: not applicable
Heterogeneity: not applicable
Test for overall effect:
0.52 (P
= 0.60)
TestZfor=overall
effect:
Z = 0.52 (P = 0.60)
Total (95% CITotal
)
(95% CI )
208
208 255
255
Total events: 147
Total events: 147 (Treatment),
141(Treatment),
(Control) 141 (Control)
2 = 7.75, df = 27 (P = 0.36); I2 =10%
2 = 7.75, df =Chi
Heterogeneity: ChiHeterogeneity:
7 (P
= 0.36); I =10%
Test for overall effect: Z = 4.05 (P = 0.000050)
Test for overall effect: Z = 4.05 (P = 0.000050)
Test for subgroup differences: Chi2 = 5.60, df = 2 (P = 0.06), I2 =64%
Test for subgroup differences: Chi2 = 5.60, df = 2 (P = 0.06), I2 =64%
0.1 0.2
0.5
0.1 0.2 Favours
0.5 placebo
1 2
Favours placebo
1
2
5
10
5 10azathioprine
Favours
Favours azathioprine
Prefontaine et al. Cochrane Database Syst Rev 2009
Thiopurines
 Dosage
 AZA 2-2.5 mg/kg/day
 6MP 1-1.5 mg/kg/day
 Safety/tolerance issues
 nausea/malaise (switch agents)
 lymphoma risk (4/10,000)
 opportunistic infections (vaccinate)
 pancreatitis (idiosyncratic)
 Myelosuppression (minimized if TPMT and
metabolites checked)
Methotrexate
 Alternative for the patient who does not tolerate or is
unresponsive to azathioprine or 6-MP
 May be used in preference to azathioprine or 6-MP in
patients with troublesome CD-related arthropathy.
 The drug should be initiated IM at a dose of 25 mg
per week and a response anticipated within 3 months
Methotrexate
 Remission rates reported up to 65% for MTX vs. 39% for placebo at
40 weeks
 Long-term open-label survival analysis has shown parenteral (but
not oral) methotrexate to be effective in maintenance of a
methotrexate-induced remission in 47% of patients with CD at 48
months
 Safety issues

hepatic fibrosis

interstitial pneumonitis

teratogenicity

nausea
Biologics
S
Anti-TNF Engineered Antibodies
Chimeric
monoclonal
antibody
Human
recombinant
antibody
Mouse
Humanized Fab’
fragment
VL
VH
No Fc
CH 1
PEG
Human
IgG1
IgG1
PEG
Infliximab
PEG = polyethylene glycol
Adalimumab
Certolizumab
pegol
N Engl J Med 1997;337:1029-35
Lancet 2002; 359: 1541–49
NEJM 2004;350:876-85
NEJM 2010;362: 1383-95
Adalimumab – induction Rx
Hanauer et al. CLASSIC-I, Gastroenterology 2006
Adalimumab – maintenance Rx
Colombel et al. CHARM, Gastroenterology 2007
Adalimumab – LOR to infliximab
Sandborn et al. GAIN, Am J Gastroenterol 2004
Can I combo adalimumab?
 No published studies specifically addressing issue of
combination therapy of adalimumab with
immunomodulator
 Sub-group analyses of major trials showed a trend
towards a beneficial effect of combo vs. monotherapy
 Generally felt to be a class effect among all anti-TNF
agents, although some experts would only use
combination therapy with infliximab
Vedolizumab
 Monoclonal antibody that binds to integrin α4β7
(LPAM-1, lymphocyte Peyer's patch adhesion molecule
1)
 Blocking the α4β7 integrin results in gut-selective anti-
inflammatory activity by way of interfering with
lymphocyte trafficking
 IV administration q8 weeks after induction dosing
 Recently FDA and EMA approved for both CD and
UC
Induction
Maintenance
Sandborn et al. NEJM 2013
Ustekinumab
 Human monoclonal antibody directed
against interleukin 12 and interleukin 23
 FDA approved for plaque psoriasis and
psoriatic arthropathy
 Off-label use for refractory CD who are
unresponsive or lost response to anti-TNF
Sandborn et al. CERTIFI, NEJM 2012
Ustekinumab – McGill experience
Kopylov, Al-Taweel et al. J Crohns Colitis 2014
CD Treatment Pyramid
Predicted disease activity
Very aggressive/
Refractory to Rx
Surgery
Ustekinumab
Vedolizumab
IMM + TNF antagonist
Moderately
aggressive/
More
difficult to
treat
Uncomplicated/
easily treated
AZA/6-MP/MTX
Get it right the
first time!
Start the correct
treatment at dx!
Systemic corticosteroids
TNF antagonists ( early intervention?)
Budesonide
Systemic corticosteroids
SSZ (colonic dx)
? No Rx
AZA, azathioprine; 6-MP, 6-mercaptopurine; MTX, methotrexate