Immunosuppressive Medications and IBD: Now and What’s Next
Stephen B. Hanauer, MD
University of Chicago
Indications for Immunosuppressives in IBD
• Crohn’s Disease– Steroid-Sparing (Maintenance)– Maintenance after Biologics
• Reduction of Immunogenicity
– Post-Surgical Maintenance
• Ulcerative Colitis– Steroid-Sparing
Anti TNF-α therapiesSurgery
Systemic corticosteroids AminosalicylatesN
on-systemic corticosteroids
Conventional approach to Induction Therapy: step-up
• Clinical approach to use “mildest” form of drug therapy to treat patients first
• Move to next step in non-responders
Dis
eas
e s
eve
rity
Time
Step-up management approach
Advantages
• Patients attain remission with less toxic therapies
• Potentially more toxic therapies reserved for more severe or refractory disease
• Minimizes risk of adverse events
• Cost sparing (short-term?)
Disadvantages
• Patients have to “earn” most effective treatments
• Decrease in quality-of-life before patients obtain optimal therapy
• Likelihood of surgery is high
• Disease is not modified
IBDs are chronic, life-long
We cannot just look at the short-term induction therapy
Long-Term Therapy for IBD is Sequential
InductionMaintenance
Maintenance Therapy is Dictated by Induction Therapy
Induction Maintenance
Aminosalicylate Aminosalicylate
Maintenance Therapy is Dictated by Induction Therapy
Induction Maintenance
CorticosteroidAminosalicylate (UC)ThiopurineMethotrexate (CD)
Maintenance Therapy is Dictated by Induction Therapy
Induction Maintenance
Cylcosporine Thiopurine
Maintenance Therapy is Dictated by Induction Therapy
Induction Maintenance
Anti-TNFThiopurine (Steroid-Naïve)Anti-TNF (Steroid-Refractory)
Maintenance Therapy is Dictated by Induction Therapy
Induction Maintenance
Natalizumab Natalizumab
“Natural History” of Disease Behavior in CD
Cosnes J et al. Inflamm Bowel Dis. 2002;8:244.
24022821620419218016815614413212010896847260483624120
0
10
20
30
40
50
60
70
80
90
100
Cum
ulat
ive
Pro
babi
lity
(%)
Patients at risk:Months
2002 552 229 95 37N =
Penetrating
StricturingInflammatory
Progression Toward Surgery
Impact of Therapy will Depend on Degree of Structural Damage & Velocity of
Progression
Cosnes J et al. Inflamm Bowel Dis. 2002;8:244.
24022821620419218016815614413212010896847260483624120
0
10
20
30
40
50
60
70
80
90
100
Cum
ulat
ive
Pro
babi
lity
(%)
Patients at risk:Months
2002 552 229 95 37N =
Penetrating
StricturingInflammatory
High Potential Low Potential
Difference between Early & Late Intervention with
Immunosuppressants
60% exposed to IS therapy
No Change in Surgery Rates
Efficacy of AZA as Crohn’s Disease Maintenance Therapy
After Steroids in Adults*
100
80
60
40
20
0
% P
atie
nts
No
t F
aili
ng
Tri
al
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Duration of Trial (months)
AZA 2.5 mg/kg per d
Placebo
*Remission induced by prednisolone tapered over 12 wk
Inclusion: Patients were not steroid dependent
p=0.001
Candy S, et al. Gut. 1995;37(4):674-678.
42%
7%
Efficacy of 6-MP as Crohn’s Disease Maintenance Therapy
After Steroids in Steroid-naïve Children
30
40
50
60
70
80
90
100
0 50 100 150 200 250 300 350 400 450 500 550 600
Days Since Remission Induction
% o
f P
ati
en
ts i
n R
em
iss
ion
P<.007
91%
53%
N=55At baseline, patients received prednisone plus either 6-MP or placebo. Steroids were tapered after induction of remission. Markowitz J et al. Gastroenterology. 2000;119:895.
6-MP
Control
Dosing Considerations with Thiopurines
AZATHIOPRINE/6-MERCAPTOPURINE
Azathioprine 6-mercaptopurine Thioinosinic 6-thioguanine (AZA) (6-MP) acid (6-TG)
6-methyl-mercaptopurine (6-MMP)
6-thiouric acid
TPMTHPRT IMDPH
GMPS
XO
Distribution of Thiopurine Methyltransferase Enzyme Activity in the Population
12
Weinshilboum.Weinshilboum. Am J Hum Genet Am J Hum Genet. 1980. 1980
88
66
44
22
00
% of Subjects/0.5 units of Activity% of Subjects/0.5 units of Activity
00 55 1010 1515 2020
Erythrocyte TPMT Activity (UErythrocyte TPMT Activity (UmLmL-1-1))
TPMTTPMTHH
TPMTTPMTHH1010
TPMTTPMTLL
TPMTTPMTHH
TPMTTPMTLL
TPMTTPMTLL
Early Evidence with Allopurinol
6-MP 6-TG
6-MMP
6-thiouric
HEPATOXICITY
↑↑ACTIVITY
INACTIVE
X0
HPRT,IMDPH,GMPS
Sparrow & Hanauer DDW 2005
CONTROVERSIES REGARDING THERAPEUTIC DRUG MONITORING
• No Prospective Data
• Time Course to AZA/6-MP Activity > 8-12 weeks– Sandborn I.V. Loading trial
• Mechanisms of Action of 6-MP?
• Relationship of 6-MMP to Bone Marrow – Also of 6-Thioguanine to Bone Marrow
• Cost Effectiveness vs. Clinical Monitoring with WBC
Indications for Therapeutic Monitoring
• Primary Dosing Regimens– Aim for target levels– Expensive
• Assessment of Non-Responders or Elevated Transaminases
– Consistent with current practices– May be more cost-effective
• Assessment of Adherence– Pediatrics
SUMMARY
• Pharmacogenitic Considerations are Important for IBD Therapeutics
• Therapeutic Drug Monitoring May Offer Improvements If:– Prospectively Demonstrated– Superior Safety and Efficacy to Clinical and
Routine Laboratory Monitoring
Optimizing Dose of ThiopurinesConsider Pharmacology & TPMT
Status
• TPMT Homozygotes– Start very low (e.g. 25 mg, 2-3 times/week)
• TPMT Heterozygotes– Start low dose (~1 mg/kg)
• TPMT Normal– Start 2.5 mg/kg
• TPMT High (abnormal LFTs, ↑6MMP)– Consider reducing dose & adding allopurinol
Feagan B, et al. N Engl J Med 2000.
Methotrexate Maintenance after Steroids in Crohn’s Disease
• Multicenter, randomized, controlled trial
• 76 steroid-dependent patients
• In remission following methotrexate 25 mg IM x 16 weeks
• Randomized to 15 mg IM or placebo x 40 weeks
Weeks since randomization
% R
emis
s ion
Methotrexate
Placebo
n=40
n=36
0 4 8 12 16 20 24 28 32 36 40
100
90
80
70
60
50
40
30
65%
39%
65% of 45% responders=30% overall
Yin & Yang of Concomitant Immunomodulators
• All biologics are immunogenic
• Antibodies (at least to infliximab)– Associated with
acute/delayed infusion reactions
– Shorter duration of response (with episodic therapy)
• Immunomodulators reduce immunogenicity across all trials
• Yet…• No difference in short- or
long-term responses to induction + maintenance therapy
• Increase toxicity– Serious infections– Risk of neoplasia
50
37
1.9
43
3.3
41
32
5.3
48
4.6
0
20
40
60
45
34
7.2
55
36
3.9
4536
5.1
53
27
5.8
0
20
40
60
ACT I 54 wk Response
ACT I 54 wk Remission
ACT I 54 wk Hosp
ACT II 30 wk Response
ACT II 30 wk Remission
ACT II 30 wk Hosp
ACCENT I 54 wk
Response
ACCENT I 54 wk
Remission
ACCENT I 54 wk Hosp
ACCENT II 54 wk
Response
ACCENT II 54 wk
Response
Do Concomitant Immune-modulators Improve Efficacy of Infliximab in CD and UC?
IMM + IMM -
All p-values = NS
% p
atie
nts
% p
atie
nts
Lichtenstein GR, et al. DDW 2007. #982
Crohn’s disease
Ulcerative colitis
Patients in remission (%)
131 136 121 39 36 36
Without IMMWith IMM
Week 56
Remission defined as CDAI <150
CHARM: Concomitant adalimumab and immunosuppressive therapy DO NOT
impact on remission at week 56
Placebo
Adalimumab 40 mg EOW, sc
Adalimumab 40 mg
q-weekly, sc
12 13
3733
39
50
0
100
Colombel et al, Gastroenterology 2007; 132: 52
Certolizumab pegol q-4w 400 mg, sc
Certolizumab pegol (3 injections) + placebo
Schreiber et al, N Engl J Med 2007; 357: 239
With IMM Without IMM
(n=86) (n=87) (n=124) (n=128)
*** ***
3339
61 64
0
100
Patients (%)
***p<0.001 CR100
PRECiSE 2: Concomitant certolizmab pegol and immunosuppressive therapy DO NOT impact on Clinical response at
week 26
- IMM - IMM+ IMM + IMM
Month 6 Month 12
P≤0.009 for all comparisons with placebo
ENACT-2 Concomitant immunosuppressive DO NOT impact on
Remission at 6 or 12 Months PlaceboPlacebo
NatalizumabNatalizumab
(111) (106) (60) (62) (111) (106) (60) (62)
Sandborn W, Colombel J-F, Enns R, et al. Presented at: DDW 2006; May 20-25, 2006; Los Angeles, CA.
31
21
54 53
30
23
5860
0
10
20
30
40
50
60
70
Per
cen
t
COMMITT: MTX plus IFX in CD (1)
Methods:• Randomized, double blind, PBO-controlled trial
– Patients with active CD on corticosteroids within last 6 weeks
– 1:1 randomization to • IFX + PBO (n=63)• IFX + MTX (dose escalation: 10 mg,10 mg, 20 mg, 25 mg) (n=63)
– Steroids withdrawn by Week 14 per protocol– IFX at 0, 2, and 6 weeks then maintenance q8W
• Primary analysis: time to treatment failure– CDAI <150, no prednisone by Week 14 and maintained to
Week 50– Relapse: CDAI increase of 70 points
Feagan B, et al. DDW 2008: #682C
COMMITT: MTX plus IFX in CD (2)
76.2
55.6
77.8
57.1
0
20
40
60
80
100
Week 14 Week 50
Pat
ien
ts i
n R
emis
sio
n o
ff S
tero
ids
(%)
MTX + IFX
PBO + IFXp=0.83
p=0.63
Feagan B, et al. DDW 2008: #682C
• No difference in ITT analysis, duration of disease <2 years, by CDAI score
• No difference in infectious AEs (58.7% MTX vs 61.9% PBO)
What about stopping Immunomodulators?
Discontinued IMM (n=40)
Continued IMM (n=40)
Patients treated with AZA, 6-MP, or MTX
plus IFX 5 mg/kg and in clinical remission for
≥6 months
Week 104
Percentage of patients requiring a change in
IFX dosing or who discontinued IFX
IMID: Impact of Concomitant Immunosuppression on the Outcome of
Maintenance Infliximab Therapy
6-MP=6-mercaptopurine; AZA=azathioprine; IFX=infliximab; IMM=immunomodulator therapy with AZA, 6-MP, or MTX; MTX=methotrexate
Van Assche G, Paintaud G, Magdelaine C, et al. Gastroenterology. 2007;132:A-103. [Abstract #734]
Randomization(N=80)
IMID: Impact of Concomitant Immunosuppression on the Outcome of Maintenance Infliximab
Therapy
Median IFX levels, Week 8 to Week 104 combined
No need for early ‘rescue’ IFX: primary endpoint
p<0.005
0
1
10
100
Continued Discontinued
IFX trough levels (μg)Cumulative survival
0 20 40 60 80 100
0.0
0.2
0.4
0.6
0.8
1.0
Time (weeks)
Log Rank (Cox): 0735; Breslow: 0.906
Continued
Discontinued
Van Asche et al, Gastroenterology 2007; 132: A-103 (No. 734)
Risks Associated With Long-term Use of Immunosuppressants (AZA/6-MP)1,2
• Overall toxicity 15%
• Pancreatitis 3.3%
• Bone marrow depression (leukopenia) 2-5%
• Allergic reactions 2%
• Drug hepatitis 0.3%
• Infectious complications 7.4%
• Malignant neoplasm 3.1%
• Opportunistic infections
• Lymphoma
– Associated with ≥fourfold increase in risk of EBV (+) lymphoma and prior treatment with AZA/6-MP
– 1 additional lymphoma will occur every 300 to 4,500 years after therapy with AZA or 6-MP, depending on patient age
– Consistent with RA reports
0
2
4
6
8
10
12
1985-1992 1993-2000
EBV (-)/AZA (+)
EBV (-)/AZA (-)
EBV (+)/AZA (+)
EBV (+)/AZA (-)
Lag time observed between AZA/6-MP treatment and lymphoma development (median, 3.5 years)
1. Present DH, Meltzer SJ, Krumholz MP, et al. Ann Intern Med. 1989;111:641-649. 2. Dayharsh GA, Loftus EV Jr, Sandborn WJ, et al. Gastroenterology. 2002;122:72-77.
Lymphoma Occurrence in IBD Patients Increasedin the 8-year Period After Introduction of AZA and 6-MP
EBV=Epstein-Barr virus
Pa
tie
nts
(%
)
Ex: from Risk Factors for Opportunistic Infections in IBD A Case-Control Study of 100 Patients (1998-2003)
Odds Ratio (95% CI)
P value
Any medication (5-ASA, AZA/6MP, Steroids, MTX, Infliximab)
3.50 (1.98-6.08) <0.0001
5-ASA 0.98 (0.61-1.56) 0.94
Corticosteroids 3.35 (1.82-6.16) <0.0001
AZA/6MP 3.07 (1.72-5.48) 0.0001
MTX 4.00 (0.36-4.11) 0.26
Infliximab 4.43(1.15-17.09)
0.03
One medication 2.65 (1.45-4.82) 0.0014
Two medications 9.66(3.31–28.19)
<0.0001Toruner M, et al. Gastroenterol. 2008.
Opportunistic infections and anti-TNF therapies :
Infliximab + Azathioprine in Patients WithActive Steroid Dependent Crohn’s Disease
• 115 pts active CD (CDAI >150) despite treatment with prednisone 10 mg/d for 6 mo
• Stratified for pre-study use of AZA/ 6-MP for > 6 mo, or no prior AZA/6-MP
• All treated with AZA 2 to 3 mg/kg or 6-MP 1 to 1.5 mg/kg
• Randomized to infliximab 5 mg/kg or placebo at 0, 2, 6 weeks
• Steroids systematically tapered• Primary endpoint: % clinical remission &
off steroids at Week 24
• No difference in outcome for AZA/6-MP treated and naive patients
3829
22
75
57
40
0
10
20
30
40
50
60
70
80
Week 12 Week 24 Week 52%
Rem
issi
on O
ff S
tero
ids
Placebo Infliximab
P<0.001
P=0.003
Lemann. Gastroenterology. 2006
P=0.04
Conventional Treatment of UC: Immunomodulators
• Immunomodulators are effective for maintenance of remission, but not induction
• Blinded, controlled clinical trial data are limited compared to CD
AZA Withdrawal in Patients With UC Who Required AZA to Achieve
RemissionRelapse Rates at 52 Weeks
59
36
0
10
20
30
40
50
60
70
% o
f P
ati
en
ts
Placebo AZA (mean dose 100 mg)
P=.04
Randomized controlled trial of patients who had been receiving AZA for 6 months Hawthorne AB et al. BMJ. 1992;305:20.
N=79
Treatment Success* After 6 Months
19
53
0
10
20
30
40
50
60
% o
f P
ati
en
ts
5-ASA 3.2 g/d (in 3 divided doses) AZA 2 mg/kg per day
AZA vs 5-ASA for Steroid-Dependent, Active UC
Ardizzone S et al. Gut. 2006;55:47.
P=.006
*Defined as clinical remission (Powell-Tuck Index Score of 0) and endoscopic remission (Baron Index Score 1) plus steroid discontinuationPatients treated with concurrent tapering dose of steroids
† 0.8 g at breakfast and lunch and 1.6 g at dinner
N=72†
Conventional Treatment: CsA
• CsA is effective for induction of remission in severe UC
• CsA has demonstrated little efficacy for maintenance of remission
• Use is limited due to significant safety concerns
Intravenous CsA: Severe Active Steroid-Refractory
UC
141313
6
0
5
10
15
20
LichtigerScore at Week
0
LichtigerScore at Week
2
Lic
hti
ger
Sco
re (
0 to
21)
Placebo CsA 4 mg/kg
N=20*Lichtiger score <10 points for 2 consecutive days
P<.001
0
82
0
10
20
30
40
50
60
70
80
90
Clinical Response at Week 2
% o
f P
atie
nts
Placebo CsA 4 mg/kg
*
Lichtiger S et al. N Engl J Med. 1994;330:1841.
CsA Use in Acute UC: Long-Term Experience
Campbell S et al. Eur J Gastroenterol Hepatol. 2005;17:79.
Oxford 1996 to 200376 patients with
severe UC
56 respondersto CsA
65%
90%
42%
66%
58%
40%
0%
20%
40%
60%
80%
100%
0 6 12 18 24 30 36 42 48 54 60 66
Months Since Initiation of Cyclosporin
CSA + 6MP/aza* (n=27)
CSA alone (n=15)
All Patients (n=42)
Avoidance of Colectomy with Azathioprine After CYSA Induction
Cohen, Stein, Hanauer. Am J Gastroenterol 1999;94(6):1587-1592
Pro
bab
ilit
y of
Avo
idin
g C
olec
tom
y
Cyclosporine as a “Bridge” to Azathioprine Maintenance in UC
Study No. CYA Initial Sustained SustainedDose Response Response Response
on AZA no AZA
Fernandez 13 4 mg/kg IV 12/13 7/8 1/4
Ramkrishna 6 1-2 mg/kg IV 5/6 4/5 0/1
Cohen 42 4 mg/kg IV 36/42 20/25 6/11
Rowe 36 2.5 mg/kg IV 26/36 7/19 5/7
Stack 22 4 mg/kg IV 20/22 7/10 5/10 ____ ___ ___
99/119(83%) 45/67(67%) 17/33(51%)
Cyclosporine Use in Acute Ulcerative Colitis: Long-Term Experience
Year 1 2 3 4 5 6 7
Percent without colectomy
67 57 48 41 31 16 12
Percent in remission
41 35 25 18 12 8 6
142 patients with severe acute UC treated with IV CyA118 (83%) responded44 patients (31%) were on AZA, 74 (52%) were started de novoAt 1 year, 23/44 (52%) of patients on AZA required colectomy compared with 12/74 (16%) starting AZA
Moskowitz. Gastroenterology 2005 Abstract
Should Biologics be used Earlier in IBD?
• Anti-TNF is more efficacious than conventional therapies
• Anti-TNFs are safer than conventional therapies (Corticosteroids)
• May be more cost-effective (over time) than conventional therapies
• Conventional Therapies Induce/Maintain Remissions in majority of patients
• Majority of patients do not need cost/toxicity risks of biologics
• Long-term safety experience in children & pregnancy
• Can we transition back to conventional immune modulators as in RA?
When to Introduce Biologics?
The “Tipping Point” may be Corticosteroids?
Challenges of InductionMaintenance 2008:
Consider the PopulationSteroid-Naïve
Steroid-InductionThiopurine/MTX Maintenance
Anti-TNF InductionThiopurine/MTX Maintenance
Challenges of InductionMaintenance 2008:
Consider the Population
Steroid-Dependent
Thiopurine/MTX Maintenance
Failure
Biologic
Challenges of InductionMaintenance 2008:
Consider the Population
Steroid-RefractoryImmunosuppressive
naïveAnti-TNF induction
Thiopurine/MTX Maintenance?
Steroid-RefractoryDespite
ImmunosuppressiveAnti-TNF induction &
MaintenanceStop Immunosuppressive
FailAnti-TNF + Switch
FailSwitch or Natalizumab
SummaryImmunosuppressives in IBD
• Most Effective as Maintenance Therapies– After Steroids– After Biologics– After Cyclosporine (UC)
• Early Aggressive Therapy is most effective• Optimal Dosing for Thiopurines Remains to be
Established– Consider Pharmacogenomics
• Role for Methotrexate Continues to Evolve• Cyclosporine for Severe/Fulminant UC• Monotherapy with Biologics appears effective
and safe
