1. Thiopurines still have a role in the management of pediatric IBD Athos Bousvaros MD, MPH Associate Director, IBD program Boston Children’s Hospital

2. Disclosures (last 12 months) Consultant – Takeda/Millennium – Dyax – Cubist – Peabody Arnold (litigation) Research support – Prometheus

3. The “Balancing Act”

4. 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)

5. 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

6. 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.

7. 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

8. Need more data on thiopurine mucosal healing in children 8 year old Crohn colitis pre-6MPTwo years later

9. 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

10. 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

11. 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

12. 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

13. 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 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 Colette Deslandres

14. 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

15. 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!

16. 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!