APDW IBD-Working Party Crohns Disease Consensus Statements 2011
Management of CD
Biological Agents
Associate Professor Rupert WL Leong
Director of Endoscopy, Concord Hospital
University of New South Wales, Sydney Australia
Quality of Evidence
• Major publication(s)
• Cochrane/ systematic reviews
• Current guidelines/ recommendations
– BSG Guidelines 2004
– AGA Position Statement 2006
– ECCO Consensus 2 2010
• Asia-Pacific studies
• Quality of evidence – mostly Western
– assumption: similar efficacy
– note pharmacogenomics eg thiopurines
– infectious diseases
Management Statement 12
Statement rationale: biological agents - indications
•There are no data that internal fidtulae respond to biologis - these need
surgical treatment
•Numbering would help.
•Surgery adjustment to anti-TNF
"Too many substatements here too....may be we should vot for substetements
example:
""Biologial agenst should be cosindiered:
a. failure of 2nd line medical treatment
b. presence of fistulizing diesases (and a quailifying stteemtn about fibritic
strictures...not been responsive)
• Maintenance of Remission
EIM
Pyoderma gangrenosum
3 months
Etanercept can precipitate uveitis
Hewitt et al Austral J Derm 2007
Management Statement 12
The indications for anti-TNF biological agents include failure
of conventional therapy in luminal disease [I-A], as well to
as
fistulizing CD [I-A] and some extra-intestinal manifestations
• conventional
steroids
[II-3,B]
of CD.
• with or without immunomodulators
• maintenance of remission
• EIM
Perianal
fistulizing CD in addition to appropriate surgical
management.
• fistulas
strictures
Text:• Anti-TNF
therapy may have limited efficacy in the
treatment of internal fistulas. Fixed fibrotic strictures do not
respond well to anti-TNF.
Management 13
Statement rationale: monotherapy or combined
•
•
•
•
•
I would not use the word synergism here. It implies a phaarmacologic
interaction. Also, the benefits of combined treatment are only present for
infliximab in very specific ircumstances. The COMMIT study showed no
benefit from infliximab plus methotrexate
The statement of efficacy should be clarified completely, then state reversed
event.
"substatements: (voting separately_
Combined therapy with infliximab and azathioprine, is useful
Combined therapy is safe"
Median serum trough IFX
IFX + AZA
IFX + placebo
13
Immunomodulator Withdrawal
• withdrawal of IM at 6 mth
– maintenance infliximab q2mth
Rescue anti-TNF
Cease anti-TNF
Van Assche Gastroenterol 2008
Azathioprine/ 6MP Withdrawal
CRP:
favours continuing immunomodulator
infliximab trough level:
favours continuing immunomodulator
Van Assche Gastroenterol 2008
Hepatosplenic T Cell
Lymphoma
Mackey J Pediatr Gastroenterol Nutr 2007
Hepatosplenic T Cell
Lymphoma
Little data from Asia
Hepatosplenic T Cell
Lymphoma
• ?increased recognition following
concern regarding anti-TNF causing
lymphoma
• ?anti-TNF reduces threshold of
developing HSTCL with thiopurines &
Crohn’s disease
• ?independent to anti-TNF
MTX
• no synergism with IFX (COMMIT)
– CD active disease induced with steroids
and IFX
– 50 week steroid-free remission
– IFX + placebo: 56%
– IFX + MTX: 57% (ns)
– abstract
Management 13
• infliximab and thiopurine
• HSTCL
Combined infliximab and thiopurine is more effective than either alone
in thiopurine-naïve patients. [I-A]
The risk-benefit balance including lymphoma-risk and opportunistic
infections need to be considered. [II-3, B]
MTX in text no data with ADA
Management 14
Statement rationale: dosing, other biologics
•
•
•
•
•
•
•
•
80mg SC then 2 weekly thereafter.
8-weekly?
"Should be 2 weekly therefore for Adalimumabs.
Certouzumis should be mentioned as well "
About adalimab, "then 8-weekly" is wrong. It should be corrected to "40mg sc
bi-weekly".
Certoluzimab and natalizumab have been adopted by US FDA
Adalimumab need 2 weekly
Infiximab and adalimumab are the only 2 clically useful biological agents
(doses given inthe paragraph belw as qualifying statements...not for voting!
%
Infliximab
(Remicade)
Hanauer et al Lancet 2002
Certolizumab Adalimumab
(Cimzia)
Schreiber et al NEJM 2007
(Humira)
Colombel et al Gastroenterol 2007
Biologics
• 4 commercially available:
– infliximab (Remicade)
– adalimumab (Humira)
– certolizumab (Cimzia) – further phase 3
– natalizumab (Tysabri) – limited use
• others under trial
– vedolizumab
– ustekinumab (Stelara) etc
– small molecule: CCR9 receptor blocker
• induction:
– ineffective: etanercept, CDP571
– ?certolizumab
• maintenance
Natalizumab
vessel wall vascular
• leukocyte trafficking
cell adhesion
molecule (VCAM)
– blocks migration of
lymphocytes to inflamed tissue
– monotherapy
– reactivation of JC virus in brain
– monitor for neuro Sx
– 7 cases
– plasma exchange
lymphocyte
progressive multifocal leukoencephalopathy (PML) alpha-4 integrin
Adelman NEJM 2005, Yousry NEJM 2006
alpha-4-beta-7 integrin inhibitor
(Vedolizumab)
• monoclonal Ab
– targets only a4b7 integrin:
– GI tract-specific
– ligand = MAdCAM (mucosal addressin
cell adhesion molecule) – expressed on
intestinal vascular endothelium
– increased expression in inflamed gut
Management 14
2
• IFX
• ADA
• other biologics
Infliximab etc
[I-A]
Remove other biologics
Management 15
• Screening and treatment for active/
latent TB and any form of sepsis
should be carried out prior to
commencing anti-TNF treatment.
•
•
•
•
•
•
Tuberculin skin tests rather than IGRA may still be acceptable due to cost
constraints
IGRA is not available in some countries like us
TB culture/PCR not done under to high supervision
"This shoud be the stetemtn.....""Active and latent tuberculosis and other
infectious colitides must be excluded prior to treatment with anti-TNF
therapy""
Others as clarifying statements"
Should we say that when ever IGRA is not available, an alternative may be
the mantoux test?
Tuberculosis
TB reporting rate per 1,000 patients
Tuberculosis
• PPD not helpful: BCG, immunosuppressed
– individual risk assessment:
Case
Annual
disease/
100,000
Anti-TNF
effect (x5)
Risk of
prophylaxis
(/100,000)
Risk/ benefit
7
35
278
Observe
Indian subcontinent >35;
UK 3 years
593
2965
278
Prophylaxis
Black African, 35-54
168
840
278
Prophylaxis
Other ethnic, >35; UK >5
years
39
195
278
Observe
White, 55-74, UK born
• serious infections:
– randomised studies: no increase in
infections
•
•
•
•
Exposure history, examination
IGRA
CXR
mucosal biopsies: TB culture, PCR
Opportunistic Infections
• Japan: RA date; n = 646 anti-TNF vs
498 on DMARDs
Revised Management 15
• Screening and treatment for active/
latent TB and any form of sepsis
should be carried out prior to
commencing anti-TNF treatment.[II3,B]
Management 16
Statement rationale: HBV screening
• Cost may be an issue in developing countries. Which vaccine
souhld be carried out also not established. (the adult vaccine
schedule is very extensive). Live vaccines (eg varicella)
BEFORE treatment may not be feasible in patients requiring
prompt treatment.
• Prior to immunomoderator, stewia, and biologics.
• Whether anti-viral prophylaxis with immunomodulator?
• this is mainly for rheumatological diseases....makes sense to
reccommend but I dont know the incidence of reactivation
• Is there any evidence for screening for Hepatitis C although
there is no vaccine or single effective anti-viral therapy?
alive
• HBV Screening
alive
died
subfulminant
hepatitis
Tx LAM
Tx LAM
Tx LAM
died
Tx LAM
Tx LAM
Tx LAM
HBV
•
•
•
•
majority HBsAg+patients
some HBsAg−, anti-HBc Ab +
variable manifestations
TNF-α central mediator of anti-HBV
responses
• reactivation (increased viral loads with
or without increased transaminases)
– some fatal hepatitis
HBV Strategies
• 1. monitor HBV, ALT: reactivation not
in everyone
• 2. prophylactic LAM/ anti-viral therapy:
reactivation unpredictable and risk of
death
– prophylaxis for 3-6 mths after cessation
of anti-TNF
HCV
• TNF-α in HCV infection differ to HBV
– serum TNF levels predict failure of
interferon therapy
– liver inflammation perpetuated
– favourable short-term safety profile
• longer term safety remains to be
proven
• ECCO: screening not routine
ECCO 2009
Management 16
Screening for HBV is recommended prior to initiation of immunosuppressive
agents.
• ?which HBV serologies
Anti-viral
prophylaxis VZV,
should be HIV
considered in HBV-positive individuals
• ?HCV,
receiving biological agents or steroids.
•
?prophylaxis
Patients with HBV on immunomodulator therapy requires monitoring for HBV
reactivation and commencement of anti-viral therapy for reactivation.
Patients should be up-to-date with specific vaccinations.
Live virus vaccinations are to be avoided for at least 3 weeks prior to
commencement of biological agents and 3 months after the last dose of
biological agents
Management 17
Statement rationale: contraindications
• nil comments
• TNFα elevated in CCF
– contraindicated
• demyelination:
– case reports
– improvement on discontinuation
Pregnancy Outcomes
Vinet E, et al. Biologic Therapy and Pregnancy Outcomes in Women With Rheumatic
Diseases. Arthritis & Rheumatism 2009. 61;5:587-92
Infliximab
Infliximab Birth Anomalies
• trisomy 18
• intestinal malrotation, tetralogy of Fallot
Vinet E, et al. Biologic Therapy and Pregnancy Outcomes in Women With Rheumatic
Diseases. Arthritis & Rheumatism 2009. 61;5:587-92
Management 17
• CCF
• demyelination
• pregnancy
Contra-indications for anti-TNF therapy include congestive cardiac failure
(NYHA Class III and IV) and demyelination disorders.
There is little data on the use of anti-TNF agents during pregnancy but it appears
to be safe.
Management 18
Statement rationale: stopping anti-TNF where cost prohibitive
• May reserve the choice for switching back to AZA
due to finacial constrain in some countries
• 3-6 month of treatment with anti-TNF for
maintenance is too short.
• Should clarify how to select patients
• Must vote for substatements
Stopping IFX
• STORI trial
– when to stop IFX?
• no inflammation on colonoscopy
• normal CRP
Episodic vs Scheduled
Maintenance
Activity
0 2
0
0 2
0
0
Episodic Dosing
Activity
0 2
6
Maintenance Dosing
14
22
30
38
46
54
Episodic vs Scheduled
Maintenance
• scheduled IFX improves Infliximab
mucosal healing (lower
CDEIS)
P =0.053
% improvement
P =0.066
Rutgeerts et al GI Endoscopy 2006
Management 18
• duration of anti-TNF
• monitoring
• scheduled maintenance
In patients who enter clinical remission, anti-TNF may be given indefinitely
Ongoing monitoring of clinical efficacy and complications is recommended at least 3-6
monthly.
Cessation of anti-TNF may be an option
Scheduled maintenance therapy is recommended rather than episodic therapy.
Management 19
Statement rationale: anti-TNF Ab, titres, cancers, sepsis
•
•
•
•
•
•
We should watch out all of the infectious signs clinically during anti-TNF
treatment.
"Should subdivide statements - use of antibody/drugs and level vs sediffuts
of anti-TNF"
Only data come from Western countries. No evidence in Asian population. It
should be described in statement.
study of the prevalence of AB to anti-TNF should be done in this region
Too many parts in this statement. First statement too stretchy. Last
statement too non-specific.
several diifrernt statements here.
IFX Titres
66
mucosal healing associated with high IFX trough levels
IFX Titres
• IFX trough levels:
– strongly correlate with the degree of
mucosal healing
• complete healing: median 6.05 (0.67 – 10.33)
• partial healing: median 3.29 (0.35 – 7.76)
• no healing: median 0.85 (0.35 – 6.62)
– IFX trough levels: useful in optimizing
therapy – allow dose adjustment
Cancers
• RCT malignancies: not increased
Cancer with Anti-TNF
• Clinical trials: lymphoma risk
– OR 3.2 (95% CI: 1.5 – 6.9) vs general population
– OR 1.7 (95% CI: 0.5 – 7.1) vs IBD on IM
• Spanish BIOBADASER national RA drug
registry (1540 patients)
– anti-TNF: 60 per 10,000 pt-yr (95% CI: 47 -75)
– control RA: 129 per 10,000 pt-yr (95% CI: 90 – 186)
Gómez-Reino JJ, Arthritis Rheum, 2003
Cancer with Anti-TNF
• Swedish RA registry: 1998 – 2006 (6366
patients)
– NO increased cancer risk with anti-TNF
– RR 0.99 (95% CI: 079 – 1.24) vs non-antiTNF
– RR 1.14 (95% CI: 1.00 – 1.30) vs non-RA
Askling et al. Arthritis Rheum 2009;60:3180-3189
Anti-TNF
• Older meta-analysis of RA studies:
– pooled OR for malignancy 3.3 (95% CI: 1.2 – 9.1)
– dose-response effect
– NNH: 154 (95% CI: 91 – 500)
Bongartz T, et al. JAMA. 2006;295:2275-2285.
• Cancer risk: highest in first 2 – 4
months of treatment
• ? pre-clinical tumours becoming
clinically manifest rather than new
cancers
• FDA warning:
– cancer risk increased with anti-TNFs
Sepsis Symptoms
Management 19
•
•
•
•
titres
antibodies
sepsis symptoms
cancers, lymphomas
Few data are available at present on the use of anti-TNF antibody titres and anti-bodies
to anti-TNF agents to optimise treatment or to explain primary non-response or
secondary loss of response to anti-TNF agents.
Patients maintained on anti-TNF agents should be aware of new TB exposure and need
to present for urgent medical attention for unexplained sepsis symptoms.
Cancers especially lymphomas are increased with anti-TNF treatments.
Management 20
Statement rationale: non-response, loss of response anti-TNF
• Re-evaluation shold be the priority over changing
treatment
• Statement in teal
• "vote for ""Primary non-response to anti-TNF
usually requires change of treatment or reevaulation of symptoms""
• the rest qualifying or clarifying statements"
Dietary Intolerances, IBS
Management 20
• exclude non-inflammatory cause of
symptom
• secondary loss of response
Primary non-response to anti-TNF usually requires changes of treatment or
re-evaluation of symptoms. Exclude symptoms from other causes, such as
stricture in the setting of Crohn’s disease, concurrent irritable bowel
syndrome, or dietary intolerances.
Repeat radiological imaging, inflammatory biomarkers (CRP, faecal
calprotectin), or ileocolonoscopy may be helpful.
Management 21
Statement rationale: managing loss of response
• nil
•
•
•
Switch IFX to ADA
IFX Failures (lost response, adverse reactions) moderate-to-severely active CD
randomised placebo or adalimumab 160/80 mg SC (n=159)
IBDQ total score and 4 IBDQ dimensional scores were assessed at baseline and week 4
Loftus et al, Gastroenterology 2007; 132 (4 Suppl. 2): A-508 (#T1288)
Management 21
•
•
•
•
•
dose increase
dose interval decrease
temporary steroids
immunomodulators
surgery
Secondary loss of response to anti-TNF treatments may require either
increase of dose of anti-TNF, decreasing dose-interval, temporary steroids,
and commencement, change or increase of immunomodulation.
Change in medical mangement or surgical management may be required.
Management 22
Statement rationale: pediatric IBD
• ?Leave out paediatrics
• I think more safety data is necessary
for pediatric patients
• Is there a age limit?
Pediatric CD Mx
Pediatric CD Mx
6MP
6MP
Management 22
• ?delete pediatric
• ?mention immunomodulators and
enteral nutrition
Long-term steroids should be avoided in the pediatric CD population.
Exclusive enteral nutrition can used to induce remission and thiopurines
are effective in the maintenance or remission.
Infliximab is indicated in the management of refractory CD.
** Review by pediatric gastroenterologist – Don Cameron, Andrew Day
Management 23
Statement rationale: surgery (covered elsewhere)
post-operative recurrence
• Balloon dilatation may be a less invasive option.
• Role of disfunctioning ilwsiy
• About post operative anti-TNF therapy, there is a
few papers now. So, we should tone down.
• No mention of endoscopic dilatation.
• Many statemtns here again
Anti-TNF in Postop CD
• IFX or placebo: within 4 weeks of
surgery
• q8wk for 1 year
• endoscopic recurrence at 1yr
– IFX: 1/11 (9%)
– placebo: 11/13 (85%, P = 0.0006)
• clinical remission
– IFX: 8/10 (80%)
– placebo: 7/13 (54%, P = 0.38)
Endoscopic dilatation
Management 23
endoscopic dilatation
For localised disease with recurrent obstruction: resection of the
diseased segment and end-to end anastomosis should be performed.
Structuloplasty is a safe alternative to resection in jejuno-ileal CD,
including ileocolonic recurrence, with similar short-term and long-term
results.
Endoscopic dilatation of accessible short strictures is an option in
specialised centres.
Anti-TNF therapy may reduce disease recurrence following CD
resectional surgery.
Management 24
Statement rationale: MAP therapy controversial
• nil
Anti-MAP Trials
Management 24
• MAP therapy
• ?antibiotic therapy in maintenance
At present, there is no definite role of anti-mycobacterial avium paratuberculosis therapy in the treatment of patients with CD.
Management 25
Statement rationale: other aspects of treatment
• what is the focus here?
Drugs in Treating IBD
FDA Class Drug
A
B
C
D
X
Adalimumab, Infliximab, 5-ASA,
metronidazole
Alendronate, Budesonide, Ciprofloxacin,
Corticosteroids, Ciclosporin, Tacrolimus
AZA, 6MP
MTX, Thalidomide
Osteoporosis
Management 25
•
•
•
•
•
fertility
pregnancy
breast feeding
nutrition
osteoporosis
Fertility, pregnancy, breast feeding, nutrition and osteoporosis are important
considerations in the management of CD.
Management 26
Statement rationale: colonic dysplasia surveillance in CD
•
•
•
•
•
Should put 8-10 years instead (more flexible)
"For UC<extensive type: 7-8 years
<Left side colm type: 10-12 years "
after 7 years.
CRC risk independent of CD should be a
condition
CRC Risk in CD
• Ekbom: n=1,655
– CD CRC RR 2.5 (95% CI: 1.3–4.3)
– Crohn’s colitis RR 5.6 (95% CI: 2.1-12.2)
• Jess (Denmark)
– SMR 1.65 (95% CI 0.2-5.92)
– 20% colectomy, 5-ASA
• meta-analysis 12 studies
– CRC RR 2.5 (95% CI 1.3-4.7)
– colonic CD RR: 4.5 (95% CI 1.3-14.9)
• CRC risk CD = UC
Surveillance in Australia
Gastroenterologist
Colorectal surgeon
(n = 60)
(n = 35)
Ulcerative Pancolitis
93%
66%
0.99
Left sided Ulcerative colitis
80%
69%
0.042
Ulcerative Proctitis
15%
40%
0.00
Terminal Ileal Crohn's Disease
7%
20%
0.03
Colonic or ileo-colonic Crohn's
80%
69%
0.10
Perianal Crohn's
13%
11%
0.11
Primary Sclerosing Cholangitis
88%
54%
0.02
P
Management 26
8-10 years
• surveillance in CD
Colonoscopy surveillance for dysplasia can be recommended for patients with
extensive Crohn’s colitis (more the one-third involvement of the colon) after 810 years (II-2, B)