Transcript Thiopurines still have a role in the management of

Thiopurines still have a role in
the management of pediatric IBD
Athos Bousvaros MD, MPH
Associate Director, IBD program
Boston Children’s Hospital
Disclosures (last 12 months)
• Consultant
– Takeda/Millennium
– Dyax
– Cubist
– Peabody Arnold (litigation)
• Research support
– Prometheus
The “Balancing Act”
Points against thiopurines
• Biologics are more effective at inducing
remission in Crohn Disease (SONIC trial)
• Biologics can rescue a subset of patients that
don’t respond to thiopurines
• Thiopurines are associated with an increased
risk of lymphoma, especially in:
– Adolescent and young adult males
– Patients on combination therapy (eg. AZA and IFX)
Why I still use thiopurines
• They work
– Monotherapy in Crohn disease
– Monotherapy in ASA refractory UC
– Combination therapy in both CD and UC
– Post-op recurrence
• Bad side effects are rare
• Biologic side effects are no bargain either
• You don’t get antibodies to thiopurines
A multicenter trial of 6MP and prednisone in children
with newly diagnosed Crohn’s disease
Markowitz et al, Gastro 2000; 119:895-902
• New onset Crohn’s
patients all given
corticosteroids, then
randomized to 1.5 mg/kg/
day 6-MP (n=27) or
placebo (n=28) for 18
months.
• Steroids tapered over 2
months
• After 18 months, 9% of
6MP patients vs. 47% of
controls had relapsed.
Thiopurines for Crohn’s - revisited in 2014
• Improve Care Now consortium
– 65 patients in different practices
– 69% remission within 180 days of thiopurine initiation
– One year follow up
• 42 % steroid free remission
• 23% continuous steroid free remission
• Problems in real world
– Variability in dosing
– Variability in metabolism and levels
– Noncompliance
Boyle et al – WJ Gastro
2014; 20:9185
Need more data on thiopurine
mucosal healing in children
8 year old Crohn colitis pre-6MP
Two years later
RISK study – anti TNF vs. IM vs. other
• Prospective observational study of 552 children with CD in
RISK cohort
• Treatment first 3 months:
– 68 got anti-TNF treatment
– 248 got early immunomodulators
– 236 got no IM or biologics
• Propensity score technique used to pick 68 equally sick
children from the bottom two groups.
• Anti-TNF treated patients had better outcomes.
– 53% vs. 24 % vs. 24%
• Does that mean every child with new onset CD should be
treated with biologics from day 1? No!
• “Further data will be required to best identify children most
likely to benefit from early treatment with anti-TNF
therapy.”
Walters et al, Gastroenterology 2014
How effective are thiopurines in children
with ulcerative colitis who don’t respond to
aminosalicylates?
• Pediatric IBD registry – 394 UC patients
• 194 treated with thiopurines within 3 months
– Excluded IFX/CyA/tacrolimus use
• One year outcome in 133 patients
– 73% avoided IFX or surgery
– 50% corticosteroid free inactive disease
Hyams et al, Am.J. Gastro 2011; 106:981
Thiopurines reduce colorectal cancer
risk in adults with UC and Crohn’s !
• Prospective cohort study in 19,486 patients
– (60% with CD, 30% receiving thiopurines).
– 2,841 with high risk colitis (>50% of colon, >10 years
of treatment).
• Over 2-3 years of followup
– 37 colorectal cancers
– 20 high grade dysplasia
• Patients on thiopurines had a much lower
likelihood of getting cancer - Hazard Ratio = 0.27
Beaugerie Gastroenterology 2013; 145:166-75
Combination therapy in both
CD and UC (adult data – remission rates)
• SONIC (Crohn disease) – Remission 26 weeks
– AZA plus infliximab – 57%
– Infliximab alone – 44%
– Antibodies to IFX – 1% (combination) vs. 15% (mono)
• UC SUCCESS (Ulcerative colitis)* – Remission 16 wks
–
–
–
–
AZA plus infliximab – 40%
Infliximab alone – 22%
Azathioprine alone – 23%
Ab to IFX – 3% (combination) vs. 19 % (mono)
*Panaccione et al, Gastro 2014;146:392
What about methotrexate?
• Data on methotrexate is limited in children,
especially as first line in new onset
pediatric Crohn’s disease.
– Most studies are on 6MP nonresponders
• One year remission rates on MTX in
children*
– 25% in Crohn’s disease
– 13% in ulcerative colitis
Colette
Deslandres
• COMMIT trial (adults) – no difference in
remission rates between IFX monotherapy
and IFX plus MTX**
*Willot et al IBD 2011 17:2521
*Feagan, Gastroenterology. 2014 146:681-688
Risks
• Thiopurines
– Pancreatitis, leukopenia, infection
– Lymphoma risk in children: 1/2221 patient-years if
on a thiopurine*
• Anti-TNF
– Infusion reactions, anaphylaxis, opportunistic lung
infections, interstitial pneumonitis, psoriasis,
hepatitis B reactivation, demyelinating disease
– LOSS OF RESPONSE
*Ashworth et al: IBD Journal 2011; 18:838
Conclusions
• Thiopurines work in many patients
– moderate Crohn disease
– ASA refractory UC
• Data on methotrexate is limited in
children.
• Serious adverse events do happen, but
are fortunately rare.
• You can always add a biologic later.
• Weigh the benefit/risk ratio of
combination treatment (at least a short
course).
• Don’t let the boogieman scare you!
Conclusions
• Thiopurines work in many patients
– Moderate Crohn’s disease
– ASA refractory UC
• Data on methotrexate is limited in
children.
• Serious adverse events do happen, but
are fortunately rare.
• You can always add a biologic later.
• Weigh the benefit/risk ratio of
combination treatment (at least a short
course).
• Don’t let the boogieman scare you!