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When can we use combination therapy for our pediatric IBD patients? Athos Bousvaros MD, MPH Advances in IBD Dec 2014.

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Presentation on theme: "When can we use combination therapy for our pediatric IBD patients? Athos Bousvaros MD, MPH Advances in IBD Dec 2014."— Presentation transcript:

1 When can we use combination therapy for our pediatric IBD patients? Athos Bousvaros MD, MPH Advances in IBD Dec 2014

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

3 Questions Should we use combination therapy in our pediatric IBD patients? If so, what kind? – Thiopurines and infliximab – Methotrexate and infliximab How does monitoring of biologic levels (therapeutic drug monitoring) impact on our decision? Is adalimumab different from infliximab? How long do we continue combination therapy?


5 The “Balancing Act”

6 Our options with biologics ProsCons Infliximab WorksAntibodies monotherapyLoss of response IFX with levelsMay work betterAntibodies Adalimumab WorksAntibodies monotherapy CombinationWorks bestLymphoma Therapy – AZA/IFX Combination WorksNo better than IFX MTX/IFXDecreased antibodymonotherapy?

7 Reading the literature on biologics, antibodies, loss of response, and drug levels

8 Adult studies

9 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

10 UC SUCCESS trial 239 adult patients randomized to: – AZA alone – 2.5 mg/kg/day – IFX alone (5mg/kg) – 0,2,6, 14 – AZA and IFX together – Double blind, double dummy design Inclusion criteria – Moderate to severe disease (Mayo score >= 6) – Stable dose of steroids allowed – No prior rx with MTX, CyA, Tacro, or rectal therapy – AZA naïve for 3 months or more Panaccione, Gastro 2014; 146:392

11 UC SUCCESS in close up Panaccione, Gastro 2014; 146:392

12 US SUCCESS results Week 16 Remission rates – 23 % AZA and IFX – 39% combination Drops in Mayo score – AZA - 3.00 – IFX - 4.3 – AZA/IFX - 5.2 Calprotectin levels lower in combination group – 170 combination – Around 400 other 2 groups SAE’s more common in the two azathioprine groups (pancreatitis, anemia, nausea, vomiting) – NO 6MP levels or TPMT assayed

13 Loss of response – natural history (Oussalah et al; AJGastro 2010) 88 patients treated with combination AZA and infliximab for at least 6 months Azathioprine withdrawn in 48 patients Probability of infliximab failure – Increasing dose, shortening interval, surgery, or hypersensitivity – 15% at 12 months – 41% between 24 and 32 months Withdrawal of AZA strongly associated with infliximab failure (hazard ratio of 7 in patients that received combination for less than 800 days)

14 COMMIT trial (MTX and IFX in Crohn) 50 week trial in adults with CD 126 patients randomized to: – IFX monotherapy – IFX and MTX (SQ, up to 25 mg/week) Primary endpoint – lack of steroid free remission at week 14, or at 50 weeks – 30 % failure in both groups However, antibodies lower in IFX + MTX – 4% (combo) vs. 20% (mono) at 1 year remission Low CRP Feagan et al Gastro 2014; 146:681-8

15 Development of antibodies to adalimumab 247 adult and pediatric patients – 205 Crohn, 42 UC 330 “loss of response events” – Suspected worsening by physician – “Definite inflammatory LOR” (identification of inflammation by labs, stool markers, or endoscopy) Of 142 “LOR events”, 38% were associated with antibodies. – Concomitant immunomodulators in about 30% – No clear impact of IM on outcome – AAA antibodies > 4 mcg/ml predicted patients who did not respond to increased dosage of IM. Yanal et al, CGH 2014, in press

16 Pediatric studies

17 Infliximab in pediatric Crohn’s (REACH trial) Children with active CD – Infliximab 5mg/kg 0,2, 6 weeks then q 2 months 88% response rate after 3 infusions 56% remission rate after 12 months However: – Concomitant immunomodulators used for duration of study REACH describes efficacy of combination therapy (mostly thiopurine) Hyams et al Gastro 2007;132:863

18 Prevalence of antibodies to infliximab in children with IBD Boston Children’s Hospital – Cross-sectional cohort of 133 children – All still receiving infliximab as per their primary physician’s dictates. – 20% had antibodies to infliximab – ATI correlated with lower IFX levels, but not (as of yet) with loss of response or infusion reactions. – ? Latency period between development of antibodies, drop in levels, and loss of response. Zitomersky et al, in press, IBD

19 Long term outcomes of pediatric infliximab therapy 259 patients – CD and UC 188 on IFX for at least 1 year – Median duration 29 months – 84% CD, 16% UC Results – Half of CD patients underwent dose intensification to maintain or recapture remission Most patients stayed on IFX (about 70% in both groups). No effect of low dose oral MTX Vahabnezhad et al, IBD 2014; 20:606

20 IFX level at week 14 may determine clinical outcome in children Prospective study of 58 IBD patients (81% CD) 13% primary nonresponse 58% in persistent remission at 1 year of therapy Median IFX level at week 14 correlated with remission (4.7 mcg/ml for patients in remission at 1 year, vs. 2.6 mcg/ml). Immunomodulators correlated with higher level, but this was not statistically significant. 26% had detectable antibodies to infliximab by week 54 Singh et al, IBD 2014; 20: 1708

21 Adalimumab in pediatric CD (Hyams et al, Gastro 2012; 143:365-74) 192 CD patients with active PCDAI (>30) – Approximately 60% on ‘immunosuppressants” – Standard induction, then hi vs. low dose Results (clinical remission, high dose) – Week 26 57% infliximab naïve, 17% if prior infliximab – Week 52 45% infliximab naïve, 19% if prior infliximab Infection rate about 5%, antibody rate only 3%

22 Summarizing Good evidence that using combination treatment with thiopurines in patients starting on infliximab – Improves clinical remission rates in CD and UC – Reduces the likelihood of antibody formation Data on combination therapy with methotrexate and infliximab is lacking – Perhaps reduction in antibody formation – More studies needed Unclear if combination treatment impacts antibody development and clinical outcomes in patients treated with adalimumab More studies are needed

23 How I like to practice Moderate Crohn’s disease treated with an immunomodulator first, then biologic if poor response. – Continuation of combination treatment (eg. AZA and inflximab) for at least 6 months – Replacement of the thiopurine with low dose MTX High risk or severe Crohn’s treated with combination therapy – Extensive disease (especially mid-small bowel disease) – Severe rectal or perianal disease – Steroid-unresponsive disease – Growth failure in mid to late puberty Patient preference is important in making the decisions.

24 Age < 18 years Beginning anti-TNF therapy No contraindication to MTX use RANDOMIZERANDOMIZE Anti-TNF plus methotrexate Anti –TNF plus placebo Week 104 assessment Steroid free remission (primary endpoint) Adverse events Patient reported outcomes Antibodies to anti-TNF Week 104 assessment Steroid free remission (primary) Adverse events Patient reported outcomes Antibodies to anti-TNF Proposed clinical trial (Kappelman, PI)


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