Transcript Update on the Medical Treatment of IBD

Update on the Medical
Treatment of Crohn’s Disease
Dahlia Awais, MD, MS
Division of Gastroenterology
University Hospitals Case Medical
Center
Outline of Topics
IBD background
– UC vs Crohn’s
– Pathogenesis
Treatment
– Risks/Benefits
Current Questions
– Evolving goals and treatment paradigms
Future Directions
Inflammatory Bowel Disease
IBD – chronic intestinal inflammation
Ulcerative Colitis
Crohn’s Disease
Ulcerative Colitis
Ulcerative Colitis
Ulcerative Colitis
Crohn’s Disease
Crohn’s Disease
Crohn’s Disease
Crohn’s Symptoms
Active Crohn’s
– Chronic or nocturnal diarrhea
– Rectal bleeding
– Abdominal pain
– Weight loss
– Fever
– Fatigue
– Extraintestinal Manifestations
Skin/eyes/joints
Crohn’s Disease
Characterized by flares alternating with
remission
– <20% unremitting
– 10% prolonged remission
More than 80% lifetime risk of surgery
Vermeire et al APT 2007; 25:3-12
Peyrin-Biroulet et al AJG 2010; 105: 289-297
Risk for 1st Surgery
Dhillon et al. AJG 2005; 100: S305
Crohn’s Disease
Previous disease activity predicts future
disease activity
– Full year of remission followed by 80%
chance of remission in following year
– Disease flare followed by 30% chance of
remission in the following year
Vermeire et al APT 2007; 25:3-12
IBD Treatment Goals c. 2011
Induce and maintain response/remission
Prevent complications
– Disease related
– Therapy related
Improve/maintain quality of life
Limit surgery
?Mucosal healing
Principles of Treatment
Treatment of active disease followed by
maintenance of remission
One size does not fit all
Risks vs benefits
Treatment Overview
Induction
–
–
–
–
–
–
Sulfasalazine
Mesalamine
Steroids
Azathioprine/6-MP
Methotrexate
Biologics
Maintenance
–
–
–
–
–
Sulfasalazine
Mesalamine
Azathioprine/6-MP
Methotrexate
Biologics
Case Presentation 1
22 yo M
– 4 week history bloody diarrhea (3-4/day)
– Mild abdominal pain
Colonoscopy and biopsies
– Mild Crohn’s colitis
Recommend oral 5-ASA
Anti-Inflammatory Drugs
5-aminosalicylate (5-ASA)
– Sulfasalazine
– Mesalamine
5-ASA
Sulfasalazine
– 3-6 g/day
– Better than placebo
~43% remission rates compared w/ placebo 30%
– Not consistently effective for sb disease
Mesalamine
– Some trials have shown benefit up to 40-55% remission
– Meta-analysis
3 placebo controlled multi-center trials
Mesalamine 4g/day
Statistically significant but not clinically significant difference
– 2005 Cochrane analysis maintenance
No different than placebo
– Widely used in clinical practice
Efficacy not clearly demonstrated in trials
Summers et al Gastro 1979; 77: 847-869
Lichtenstein et al AJG 2009; 104: 465-483
Akobeng et al Cochrane Database of Systematic Reviews 2009
5-ASA Risks
Sulfasalazine
–
–
–
–
–
–
–
–
–
Headache
Nausea/vomiting
Rash
Folate malabsorption
Reversible oligospermia
Pancreatitis
Bone marrow suppression
Paradoxical exacerbation
Interstitial nephritis
Mesalamine
– Headache
– Nausea
– Rash
– Pancreatitis
– Paradoxical exacerbation
– Interstial nephritis
Interstitial Nephritis
Medicolegal
Case reports (rare)
– First report 1989
– UK GPRD
130 of 19,020 5-ASA users w/ IBD
0.17 cases per 100 patients per year
Ref cohort .08 cases per 100 patients per year
Idiosyncratic (mechanism unknown)
Inform patient prior to starting
“Monitoring” recommended package insert
– Cr
– ?effective, ?cost-effective
Gisbert et al IBD 2007; 13: 629-38
Van Staa et al Gastroenterology 2004; 126: 1733-9
Case Presentation 2
33 yo M w/ 1 yr hx Crohn’s
– Previously treated w/ steroids and mesalamine
– Abdominal pain, diarrhea controlled on steroids
Colonoscopy
– Inflammation and ulcers in TI and colon
– Biopsies c/w ileo-colonic Crohn’s
MRI-e
– No stricture/fistula/abscess
Recommend azathioprine
Corticosteroids
IV: hydrocortisone, methylprednisolone
Oral: prednisolone, prednisone, budesonide
Budesonide
– Topically active glucocorticoid
– Limited systemic bioavailability
Less toxicity
– Ileal and right sided colonic disease
– Short term efficacy less than conventional steroids
(~15%)
– Best combination of short term efficacy and safety
Seow et al Cochrane Database of Systematic Reviews 2005
Corticosteroids
Very effective at
inducing remission
– 30d pop based study
Complete
Remission
Pred 4060 mg
Placebo controlled
trials
– 50-70% remission
over 8-17wks pred 40
Not for maintenance
Faubion et al Gastro 2001; 121: 255-260
Lichtenstein et al AJG 2009; 104: 465-483
Steinhart et al Cochrane Database 2003
58%
Partial
Response
26%
No
Response
16%
Corticosteroids Risks
Cataracts
Glaucoma
Diabetes
Weight gain
Hypertension
Osteopenia/Osteoporosis
Acne
Mood/sleep disturbances
Infection
Immunomodulator Drugs
Azathioprine/6-MP
Azathioprine/6-MP
100
90
80
70
60
50
40
30
20
10
0
65
54
33
36
Aza-6MP
Placebo
p
es
a
Sp
se
on
d
oi
er
St
R
g
rin
Perfontaine et al,Cochrane Database of Systematic Reviews 2010
Azathioprine Risks
BM – Leukopenia (25%)
Hepatotoxicity (rare)
Pancreatitis (3%)
Drug intolerance (1015%)
–
–
–
–
Fatigue
Nausea
Flu-like
Hypersensitivity rxn
Infection (2-3:1)
– Viral- HSV, CMV, EBV
Lymphoma (~4x)
Lymphoma
Non-Hodgkins lymphoma
– US annual incidence 2/10,000
– Lymphoma risk increases with age
Number needed on Azathioprine to cause 1 add’l
lymphoma/year
– Age 20 : NNH ~4300
– Age 70: NNH ~350
Hepatosplenic T cell lymphoma
–
–
–
–
Young males
16 cases with 6MP/AZA alone
20 cases with 6MP/AZA + anti-TNF
>99.99% will not have this complication
Kandiel et al Gut 2005; 54: 1121-5
Kotlyar et al AJG 2010; 105: 2299
Methotrexate
Methotrexate
– Well documented effectiveness in steroid
dependent Crohn’s
Induction: MTX 25mg IM/week x16wks
– 39% vs 19% (placebo) in clinical remission
Maintenance: MTX 15 mg IM/week
– 65% vs 39% maintenance of steroid free remission at
40wks
Feagan et al NEJM 1995
Feagan et al NEJM 2000
MTX Risks
Methotrexate
– Nausea
– Fatigue/malaise
– Hepatotoxicity
Abnl LFT’s ~25%
Fibrosis/cirrhosis rare
– BM suppression
– Hypersensitivity pneumonitis
1% of patients
– Teratogen
– Increased risk of infection
– Lymphoma risk is rare
Case Presentation 3
26 yo F w/ 2 yr hx Crohn’s
– Previously treated with steroids and AZA
– Abdominal pain, diarrhea, perianal fistula
Colonoscopy
– Inflammation and ulcers in colon and TI
MRI-e
– No stricture, no abscess
Recommend anti-TNF
Anti-TNF’s
Infliximab
Adalimumab
Certolizumab
● FDA approved 1998
● FDA approved 2007
● FDA approved 2008
● Mouse chimeric
monoclonal Ab
● Fully human
monoclonal Ab
● Pegylated humanized
Fab fragment
● IV (0, 2, 6, then
q8wk)
● SQ q2wks (loading 4
pens, then 2 pens, then
1 pen)
● SQ (0, 2, 4, then
q4wk)
● 5 mg/kg
● Each pen 40 mg
● 400 mg
Anti-TNF Therapies
Patients %
ACCENT I
Infliximab
10 0
80
60
40
20
CHARM
Adalimumab
39
P<.003
21
0
Wk 2
Wk 30
Response Remission
Patients %
100
90
80
70
60
50
40
30
58
Precise 2
Certolizumab
Wk 30
Remission
Placebo
Patients % 100
58
40
P<.001
17
20
10
0
Wk 4
Wk 26
Wk 26
Response Remission Remission
Placebo
Hanauer et al Lancet 2002; 359:1541-49
Colombel et al Gastroenterology 2007; 132: 52-65
Schreiber et al NEJM 2007; 357: 239-50
90
80
70
60
50
40
30
20
10
0
64
48
P<.001
29
Wk 6
Wk 26
Wk 26
Response Remission Remission
Placebo
Benefits
Steroid free remission
Improved quality of life
Decreased hospitalizations
Decreased need for surgeries
Improved mucosal healing
Lichtenstein et al Gastroenterology 2005; 128: 862-9
Risks of Anti-TNF’s
Infusion Reaction (5%)
Infection
– Reactivation TB, HBV
– Sepsis
– OI’s
Lymphoma
Demyelinating d/o (rare)
Hepatotoxicity (rare)
Drug induced lupus (<1%)
Natalizumab
Natalizumab is a fully humanized antibody against alpha4 integrin
Prevents inflammatory white blood cells from migrating
into tissue
Can be used when patient has failed at least one antiTNF medication
Cannot be combined with other immunosuppressants
– Must taper off steroids within 6 months
Administered intravenously
Given every 4 weeks
Dose is 300 mg
Natalizumab
Patients %
50
45
40
35
30
25
20
15
10
5
0
48
32
Targan et al Gastro 2007; 132: 167283
26
16
Placebo
Natalizumab
Risks of Natalizumab
Infection
PML (1/1000)
– Opportunistic, demyelinating brain d/o
– Infection of oligodendrocytes by reactivation
of JC virus
– 50% mortality; persistent neurologic damage
– Dec 2010 79 cases/75,500 pts
Most in MS
Historical Perspective
Early 1900’s
– “slop diets”
– “vaccines”
1940
– Sulfasalazine
– Penicillin
1950’s
– ACTH
1960’s
– 6-MP
1970’s
– Sulfa-free aminosalicylates
1998
– Infliximab
– Beginning of the biologic era
Current Questions
Step Up vs Top Down
Mucosal Healing
Combination vs Monotherapy
Step up vs Top Down
Step up vs Top Down
Step up vs Top Down
Mucosal Healing
ACCENT I substudy
– Mucosal healing
associated with fewer
Crohn’s related
hospitalizations
75
Rutgeerts et al GIE 2006; 63:433-42
Crohn’s Disease Related
Hospitalizations
Healing at
Healing at
No
both visits
1 visit
healing
0/9 (0)
3/16
(18.8)
14/50
(28)
Mucosal Healing
Baert et al Gastro 2010; 138: 463-8
Combination vs Monotherapy
Steroid Free Clinical
Remission at week 26
100
80
56.8
60
44.4
30
40
Aza
Infliximab
Combination
20
0
n
io
t
na
ab
m
xi
bi
om
C
fli
In
za
A
Colombel et al NEJM 2010; 362: 1383-95
Future Goals
Predict individual prognosis
– Phenotype and risk assessment
Treatment based on risk
– More aggressive therapy to those with more
aggressive
Future Directions
Need for novel therapies
Current biologic therapies have
– Decreased hospitalizations and surgeries
– Improved QoL
But…
– Up to one-third do not respond
– Many lose response or develop intolerance
Safety concerns
– Opportunistic infections
– Malignancy
– PML (Natalizumab)
Future Directions
Oral
Less expensive
New mechanisms of drug action