ADVANCES IN
INFLAMMATORY BOWEL
DISEASE
HOPE FOR THE CURE –
WHEN VISION FOSTERS PROGRESS
Seymour Katz,M.D.
Clinical Professor of Medicine
Albert Einstein College of Medicine
CHOICES IN INFLAMMATORY
BOWEL DISEASE
Binders
Folders
Restrict Access
Open Opportunities
Choose “Folders”
THERAPY
5-ASA, steroids, surgery
Immunomodulators
(6-MP/AZA/MTX)
Biologics/simple compound (anti-TNF antibodies, anti
alpha-4 B7 integrins, anti-IL17/23, antiMadCAM/VCAM, anti-IL13,ip10, Apheresis, herbals)
5-ASA Site of Release per Design of Various Delivery Systems
History of More-Difficult-to-Treat Disease Predicts Response
to Higher Dose for Moderate UC
ASCEND I and II1
Previous Therapy
≥2 Medications
51
Steroids
Rectal
therapies
Oral
5-ASAs
0
49
53
ASCEND III2
71*
72*
58
64
54
70
61
72*
67*
54
20 40 60 80 100 0
70*
70
64
20 40 60 80 100
Patients With Treatment Success at Week 6 (%)
2.4 g/day delayed-release mesalamine†
4.8 g/day delayed-release mesalamine†
* P<0.05; †Asacol
1. Hanauer SB et al. Gastroenterology. 2008;134 (Suppl 1):A490. Abstract T1130.
2. Sandborn WJ et al. Gastroenterology 2008;134 (Suppl 1):A99. Abstract 702.
Safety Considerations of 5-ASA
Agents
• Nephrotoxicity
–
–
–
–
Nephrotoxicity rate 0.26% per patient-year1
Most often reported within the first 12 months of therapy1
May be idiosyncratic rather than dose-related1
Caution recommended when used in patients with known
(or history of) renal disease2,3
– FDA recommends monitoring BUN/serum creatinine
– Timely recognition of renal impairment and prompt
discontinuation of 5-ASA in affected patients is important1
•
Pregnancy/breastfeeding4
– Safety in pregnancy demonstrated in several trials
– Milk: serum ratios considered acceptably low
– Considered safe for use in pregnancy and breastfeeding when indicated
1. Gisbert JP et al. Inflamm Bowel Dis. 2007;13:629.
2. Asacol [prescribing information] Procter & Gamble Pharmaceuticals; Sep 2006.
3. Lialda (delayed release mesalamine) [package insert]. Wayne, PA: Shire USA; Jan 2007.
4. Kane S. Gastroenterol Clin N Am. 2003;32:323.
Most UC Patients Do Not
Require Corticosteroids
Population-Based Cohort in
Olmsted County, MN From 1970–1993
Did not receive
corticosteroids
63/183
(34%)
120/183
(66%)
Received
corticosteroids
29% patients who
begin steroids
undergo surgery
within 1 year
Faubion WA et al. Gastroenterology. 2001;121:255.
Budesonide MMX 9 mg in UC
• Budesonide MMX 9 mg
– not statistically significant for 6 mg
– no A/E differences
Remission
Budesonide MMX
Placebo
17.9%
7.4% (p = 0.0143)
• Conclusion: Seemingly safe and achieved a
modest remission of 17.3%.
Sandborn WJ, et al. DDW 2011. Abstract 746
Cancer Risk and IBD
• No increased risk with proctitis2
• Cumulative Ca rate (3 centers) for CUC = 7.2% @ 20
years, 16.5% @ 30 years
Conclusion: Similar risk of CD as with CUC3,4
Colon Cancer Prevention in UC
• 80% reduction in dysplasia or Ca in URSO group with
sclerosing cholangitis5
• 81% reduction with “regular” 5-ASA use.6
2 Ekbom
A, Helmick C, Zack M, et al. N Engl J Med 1990; 323: 1228-33
FC, Truelove SC. Gut 1964; 5:15-22
4 Gyde SN, Prior P, Allan RN, et al. Gut 1988;29:206-17
5 Pardi S. Gastroenterology 2003; 124:889-893
6 Eaden JA, Abrams K, Ekborn A, et al. Aliment Parmacol Ther 2000; 14:145-153
3 Edwards
Immunomodulators
•
•
•
•
•
•
AZA and 6-MP
Effective maintenance agents
Response slow (816 weeks)
Not tolerated by about 15%
of patients
Only about half of patients responsive to
AZA/6-MP for steroid refractory or
steroid-dependent disease
About 5%10% relapse despite treatment
Safety/tolerance issues: nausea/malaise,
lymphoma risk, opportunistic infections,
pancreatitis, myelosuppression
•
•
•
•
•
Rutgeerts P et al. Rev Gastroenterol Disord. 2004;4(Suppl 3):S3S9.
Nielsen OH et al. Aliment Pharmacol Ther. 2001;15:1699–1708.
Korelitz BI, Present DH. N Engl J Med. 1995;333:600–601.
Methotrexate
An alternative for patients not
responding to or intolerant of
AZA/6-MP
Effective when given IM or SC
Response over 8 to 16 weeks
Effective maintenance agent
Safety issues: hepatic fibrosis,
interstitial pneumonitis,
teratogenicity, nausea
High-grade lesions (%)
Exposed to any
immunosuppressant
OR 3.1 (1.4–6.5); p=0.005
100
80
60
40
20
0
63.0
33.3
14.6
Exposed
Nonexposed
Control
p=0.01 exposed aza/6-MP
25
20
15
10
5
0
19.6
12.0
Exposed
Nonexposed
8.4
Control
Kane S, et al. DDW 2006, Los Angeles. Abstract #16
Women >1 abnormal pap (%)
Any abnormal pap Hx (%)
Use of Immunosuppressants: Higher incidence of
abnormal Pap smears in women with IBD (1)
Exposed to aza/6-MP
OR 2.9 (1.2-4.1); p=0.02
100
80
60
40
20
0
44.6
22.0
Exposed
Non-exposed
Conclusions:
• Women with IBD carry a higher risk for
clinically important cervical lesions than
healthy controls
• The effect of immunomodulator use
increases this risk
• Women with IBD are appropriate candidates
for inclusion under ACOG guidelines for
increased cancer screening
Ulcerative Colitis and
Combination Treatment
• “Success trial” = “Sonic” for Ulcerative Colitis
IFX +
AZA
IFX
AZA
Steroid-free remission
40%
24%
24%
Response
77%
69%
50%
Mucosal Healing
63%
55%
37%
• No significant change between AZA or IFX alone,
therefore, supports combination treatment in 231 patients
but not naïve to immunomodulators.
• Glucocorticosteroid failures had greater success with
combination therapy (40%) versus Infliximab (20%)
versus AZA (20%).
Panccione R et al. DDW 2011. Abstract 835
MLN0002 is More Selective than Either TNF or 4 Antagonists
Why 47 integrin constitutes a preferred molecular target in IBD
Anti-TNF agents
Remicade®
(infliximab)
Humira®
(adalimumab)
• Approved for RA
• Anti-TNF therapy
• May worsens CHF
• Hematologic
abnormalities
• Increases risk of
infections such as
TB and sepsis
• Potentially
increases cancer
risk
• Approved for RA,
psoriasis, Crohn’s
Remicade® (Infliximab)
Centicor, Inc. Product
Information, April 2007
• Anti-TNF therapy
• May worsens CHF
• Increases risk of
infections such as
TB and sepsis
Pan 4 inhibitor
47 inhibitor
Tysabri ®
MLN0002
Phase III
(natalizumab)
• Approved in MS
• Inhibits 41(VLA4)-VCAM
& 47-MAdCAM interactions
• VCAM broadly expressed1
• Increased risk of PML
• Increased liver toxicity
• Increased risk of Infection
• Potentially
increases cancer
risk
Humira® (adalimumab) Abbott
Lab, Product Information,
February 2007
1.Bosco MC et al. J Biol Chem
1992;267;8366
Tysarbri® (natalizumab) Biogen
Idec, Inc. Product Information, 2007
• Studied in IBD
• Inhibits 47-MAdCAM
interactions only
• MAdCAM-1 selectively
expressed in gut
mucosa
• Not expected to cause
systemic immune
suppression
• Not expected to perturb
CNS immune
surveillance or cause
PML
MNL0002 Millennium
Pharmaceuticals, Inc. Data on File
Oral Janus Kinase Inhibitor
• Inhibiting JAK 1 and 3 (which signals IL-2, -4,
-7, -9, -15, and –21) in 139 patients showed
NO value in Crohns although response in CRP,
and fecal calprotectin.1
• A dose dependent response did occur in
ulcerative colitis patients.2
1. Sandborn WJ, et al. DDW 2011. Abstract 745
2. Sandborn WJ, et al. DDW 2011. Abstract 594
RhuMab 7 in UC
• RhuMAb 7 is a humanized monoclonal
antibody to 7 of the integrins 47 and E7
given as a single dose or placebo side in a 4:1
ratio
RhuMab 7
Placebo
Response
10/15
2/3
Remission
3/15
0/3
– 65% of 48 patients had prior Infliximab exposure.
Rutgeerts P, et al. DDW 2011. Abstract 748
Curcumin for long-term
maintenance therapy in patients
with UC
Background
• Pharmacologically active
phytochemical derived from turmeric
• Suppresses NF-kB
Study design
• Multicenter, double-blinded, placebo-controlled trial
• Patients with quiescent UC (CAI ≤4 for 4 weeks)
randomized to curcumin 2g/day (n=45) or placebo (n=44)
• Continued on sulfasalazine or 5-ASA
• Primary analysis: Relapse rates by 6 months
Hanai H, et al. DDW 2006, #572
Budesonide in Active Ileal/
Right Colonic Crohn’s Disease
Budesonide CIR 9 mg
Mesalamine 4 g
Prednisolone 40 mg
Placebo
Patients in remission (%)
80
66
60
53
62
51
36
40
20
20
0
10 weeks1
8 weeks2
CIR = controlled ileal release
1. Rutgeerts P et al. N Engl J Med. 1994;331:842845.
2. Greenberg GR et al. N Engl J Med. 1994;331:836 841.
3. Thomsen OO et al. N Engl J Med. 1998;339:370 374.
16 weeks3
Biologic Therapy:
Mucosal Healing vs. Clinical
Remission
Adverse events
Risks vs. Benefits
Symptom relief vs. deep mucosal
healing
Anti-TNF Engineered
Antibodies
Chimeric
monoclonal
antibody
Humanized
Fab’
fragment
Human
recombinant
antibody
VH
VL
CH1
No Fc
Mouse
PEG
Human
IgG1
IgG1
PEG
Infliximab
PEG = polyethylene glycol
Adalimumab
Certolizumab
pegol
ACCENT I
Proportion of Patients (%)
Clinical Rates at Week 30 and
Week 54
100
80
Response Rate
OR, 95% CI
(1.53, 0.81-2.87)
Hospitalizations
Remission Rate
OR, 95% CI
(1.46, 0.79-2.71)
OR, 95% CI
(1.71, 0.93-3.17)
OR, 95% CI
(1.24, 0.66-2.35)
63
60
53
52
50
41
39
40
37
32
20
1.9 5.3
0
Week 30
Week 54
Week 30
Immunos
Week 54
No Immunos
Week 54
Closer look at the Mayo experience with
opportunistic infections
Herpes zoster
Candida albicans
Herpes Simplex
CMV
EBV
Histoplasmosis
Blastomycosis
Streptococcus
E. Coli
Mycobacterium marinum
Mycobacterium fortuitum
Cryptococcus
Mycobacterium gordonae
28
26
18
12
8
2
1
1
1
1
1
1
1
Toruner et al. Gastro 2008;134:929
20 year old male receiving anti-TNF + Immunomodulator Therapy for 1 year
Risk of Developing NH Lymphoma
IM medication
monotherapy
Risk with
without
combination
therapy
Incidence and risk of anti-TNF therapy-induced psoriasislike reactions in CD
Retrospective database* analysis to assess incidence and risk of
developing skin lesions while undergoing anti-TNF therapy
Anti-TNF treatment
Patients with psoriasislike reactions (n/total)
Incidence (%)
Cimzia® (certolizumab pegol) n=34
0/34
0
IFX n=118
2/118
1.6
ADA n=80
2/80
2.5
Mean patient age: 46.25 years; Mean duration of CD prior to anti-TNF therapy: 17.25 years; Mean duration of antiTNF therapy: 23.7 months (range: 0.75-60 months)
While all of the skin lesions resolved upon discontinuation
(mean 10 weeks, range 4-16), 2 patients required narrowband
UVB light therapy in addition to medical therapy
*COBI: Consortium on Outcomes of Biologic Therapy in Inflammatory Bowel Disease
Parian et al. DDW 2010; Abstract W1199
New Paradigm for Treating Individuals with Crohn’s Disease and UC:
Match the aggressiveness of treatment with predicted aggressiveness of
disease, and match treatment with precise mechanism of disease
Predicted disease activity
Very aggressive/
Refractory to Rx
Surgery
Bowel rest (SB)
Cyclosporine, Natalizumab
TNF antagonist
Moderately
aggressive/M
ore difficult
to treat
AZA/6-MP/MTX
Get it right the
first time!
Start the correct
treatment at dx!
Systemic corticosteroids
TNF antagonists ( early intervention?)
Topical or rapidly metabolized corticosteroids
Uncomplicated/
easily treated
Antibiotics (Crohn’s colitis)
ASA (colitis)
ASA, aminosalicylates; AZA, azathioprine; 6-MP, 6-mercaptopurine; MTX, methotrexate
Weighing the Value of
Top-Down Therapy
Benefits
• Early promotion of
mucosal healing to
prevent complications
– Evidence of
6-MP/AZA and
infliximab promoting
mucosal healing
Lichtenstein GR et al. Inflamm Bowel Dis. 2004;10:S2–S10.
Caprilli R et al. Digestive Liver Dis. 2005;37:973–979.
Disadvantages
• Serious side effects
• Development of
antibodies (biologics)
• Cost
• Majority of patients do not
require more potent
treatments initially
Remission With No Corticosteroid Therapy
Top-Down vs Step-Up
Top-Down
Step-Up
Patients in Remission (%)
80
P < 0.001
P = 0.006
P = 0.03
P = 0.80
P = 0.43
Week 14
Week 26
Week 52
Week 78
Week 104
60
40
20
0
D’Haens GD, et al. Lancet. 2008;371:660–667.
Crohn’s disease and
Ustekinumab
• Ustekinumab (UST) = monoclonal anti-IL12 / IL23p40
UST
Placebo
Induction
39.7%
23.5%
Maintenance
41.7%
27.4%
• Induction: 6 mg/kgClinical response at week 6 vs. placebo
no remission value
• Maintenance: Of these 41.7% in remission at week 22 vs.
27.4% placebo 69.4% in response vs. 42.5% placebo
• Generally, more difficult patients:
– Infliximab failures
– Higher CDAI at entry than most studies
Sandborn WJ, et al. DDW 2011. Abstract 592
Progressive MultifocaI
Leukoencephalopathy
• 3 cases of PML
• 2 years of combined
natalizumab/beta
interferon therapyone fatality
• FDA review:
voluntary suspension
of the program (9/05
resubmitted BLA)
Risks vs. Benefits
Risks:
• Infection – vigilance regarding: C. diff., CMV,
TBC; vaccination update.
• Lymphoma – true for all biologic / IMD (4x), esp.
males < 30 with HSTCL
• M.S.
• Lupus
• Require labs: every 4 months, retest TBC
annually
Benefits:
Q: Benefits with biologic / IMD counseling?
A: Yes, better result, less A/E
Who Should Take
Immunosuppressant / Biologic
Therapy?
Q: Does the patient’s disease severity require IMD /
Biologic?
A: Appropriate for moderate to severe IBD failing
conventional Rx. or steroid-depending.
•
NOT if:
1.
2.
3.
4.
5.
•
Active (i.e. untreated) infection
Untreated malignancies (melanoma, lymphoma, renal cell Ca,
lung Ca, or presently in active chemotherapy).
Uncontrolled CHF
Neurologic disease (M.S., autoimmune neurological disease)
Fibrostenotic “strictures”: surgery required
YES if:
1.
Proven active IBD and NOT IBS, bacterial overgrowth
mimicking IBD pain / diarrhea.
Discussion before Biologic /
IMD
• Is disease severe enough to warrant biologic / IMD?
• Can patient tolerate A/E?
• Is patient “psychologically” accepting of Rx.? (i.e.
“too dangerous”, non-compliant with schedule)
• Will patient’s health insurance cover Rx.?
• Is MD’s staff prepared to assist with insurance
obstacles?
• Comment: NO “ONE SIZE FITS ALL” – Need to
Individualize therapy
UNIMAGINABLE ADVANCES
• Now:
– 124 genetic loci in IBD
•
•
•
•
Gene signatures: NPC1L1, TAF5L and
FOLH1 distinguishes Ileal in CD/UC
24 gene ratios highest in IBD>IBS
IRGM rs 10065172CD
– Microbiome
– Biomarkers
• Diagnostic
–
–
–
–
Goal:
Platform for individualizing
therapy
• Predict response to
therapy
PR3-ANCA only found in UC patients
Anti-CBir1, anti-OmpC, anti-I2 found in CD
Fecal calprotectin, lactoferrin
Anti-Glycan antibodies (gASCA, ACCA, ALCA and
AMCA) bot not in African-Americans
The Vision
• Define functions of selected IBD-related genes.
Of the124 genes associated with Crohn’s and UC
how they increase risk is unknown.
• Identify biomarkers and genes that will help
predict at the time of diagnosis when child will
develop severe vs. mild Crohn’s disease and an
individual’s response to different therapies.
Microbiome:
• Familial influence on Microbione composition: early
colonization or early diet change more important
than genetic background of host
• Diet dramatically changes bacterial composition and
gene expression
• Selective manipulation of the microbial composition
and/or function in individual patients could
revolutionize treatment of IBD
“OLDER” IBD PATIENT
THERAPY
• Distinguish: “fit” from “frail” elderly
– “Fit” – don’t exclude based on age
– Frail” – decrease mobility, polypharmacy, comorbidity,
decrease cognition
• Therefore, limit goals, don’t DESTABILIZE
Fit
Frail
Vs.
Layers of Care for the Older IBD Patient
COMORBIDITY
POLYPHARMACY
MOBILITY
COGNITION
IBD
53
IBD of Elderly: “Worse Outcomes”
(U.S. Data Base)
• Greater in hospital mortality OR 3.91 (95% CI 2.5 – 6.11) after
adjusting for comorbidities
• 15% of IBD pts on NIS survey > 65 years accounted for 25% of
IBD hospitalizations
• Greater surgical rate if fistula postoperative with increase LOS1
• Bimodal Peak: (European Data Base)
o C.D. greater incidence in young than “Old” IBD pts
• Reason: Environmental
• Increased hospitalizations: C.D. for younger / U.C. older pts2
1. Ananthakrishnan AN, et al. Inflamm Bowel Dis
2009;15:182-9
2. Sonnenberg,A. Inflamm Bowel Dis 2010;16:452-7
Overzealous Colonoscopy
Screening in the Elderly
• 24,071 patients with negative initial screening
colonoscopy
– 45.6% ages 74-79 y.o. had repeat exam < 7 years
– 32% ages 80 years or older had repeat exam < 7 years
• U.S. Preventive Services Task Force1: No routine
screening if 75 to 84; against any screening > 85 y.o.
• 40% > 70 y.o. missed follow-up colonoscopy if
(+)FOBT.
– Of these with follow-up colonoscopy: 10% complications
– If missed follow-up colonoscopy: 46% positive in < 5 years,
but 3 died of colorectal cancer.2
1. Goodwin JS, Singh A, Reddy N et al. Arch Intern Med
2011
2. Kistler CE, Kirby KA, Lee D, et al. Arch Intern Med
2011
CONCLUSION
• “HOPE PREVAILS”