Efficacy and Safety of Treatment for Pediatric IBD

Transcription

1 Efficacy and Safety of Treatment for Pediatric IBD Andrew B. Grossman MD Co-Director, Center for Pediatric Inflammatory Bowel Disease Associate Professor of Clinical Pediatrics Division of Gastroenterology, Hepatology, and Nutrition

2 Treatment of Pediatric IBD Goals Improve growth and nutrition Improve quality of life Maximize therapeutic response Minimize toxicity Prevent disease complications Mucosal healing Promote psychological health

3 5-ASA Delivery Systems PENTASA ASACOL/DELZICOL/LIALDA/APRISO COLAZAL/AZULFIDINE/DIPENTUM ENEMA SUPP JEJUNUM / ILEUM / ASCENDING / DESCENDING / SIGMOID / RECTUM SMALL BOWEL COLON

4 Efficacy of 5-ASA s Ulcerative Colitis Oral therapy effective for induction and maintenance of remission Rectal, oral + rectal More effective than just oral for distal disease Crohn s disease Efficacy unclear for induction or maintenance of remission

5 Antibiotics Decrease inflammation by changing or eliminating bacteria in GI tract Multiple indications for Crohn s Perianal disease Abscess Prevent post-operative recurrence Treatment of mild or moderate disease Flagyl (metronidazole) Cipro (ciprofloxacin) Ulcerative colitis Triple or quadruple antibiotics for refractory severe UC* *Turner D, et al. J Crohns Colitis 2014; 8:

6 Probiotics Live microorganisms Alter flora of gut Promote more favorable bacteria inflammation Many different preparations UC Effective, particularly for pouchitis Crohn s Not proven effective

7 Systemic Corticosteroids Oral (prednisone), IV (Solumedrol), or rectal Suppress active inflammation Indication: Acute UC or Crohn s flare Provide immediate symptomatic relief Do not promote healing of GI tract Not indicated for maintenance therapy Lose efficacy, side effects

8 Corticosteroids Common Side Effects Growth retardation Contribution to bone mineral density Excessive weight gain Cosmetic Acne, moon facies, hirsutism Psychological Sleep disturbance, mood instability Increased risk of infection

9 Budesonide

10 Immunomodulators Suppress immune response that triggers intestinal damage in IBD Require longer period of time for efficacy Steroid sparing effects Used alone and in combination with biological therapies Imuran (azathioprine) Purinethol (6-MP) Methotrexate No live vaccines

11 6-MP/Imuran Oral medication administered every night Requires 3-4 months for maximal efficacy Effective for Crohn s Disease and UC Maintenance of remission Decrease in steroid requirements Perianal disease? Prevention/treatment of post-operative recurrence

12 Methotrexate Better studied in Crohn s disease May improve growth, perianal disease Administered once weekly Subcutaneous injection vs. oral Laboratory monitoring required Requires 6-8 weeks for efficacy Faster onset of action compared to 6-MP Does not require monitoring of metabolites

13 6-MP/AZA and MTX Adverse Effects Nausea 6-MP/AZA white blood cell count Liver toxicity Pancreatitis Increased infection risk Increased skin cancer risk Slightly increased lymphoma risk Methotrexate Nausea white blood cell count Liver toxicity Poor appetite Increased infection risk Reaction at injection site No documented increased cancer risk Teratogenic

14 Enteral Nutritional Therapy TO BE DISCUSSED LATER!

15 Biologic Therapies Pro-inflammatory cytokines contribute to inflammation in IBD Remicade (infliximab) TNFα is elevated in IBD patients Biologics block and neutralize cytokines Used to treat moderate to severe Crohn s disease and ulcerative colitis 75% Human Humira (adalimumab) 100% Human

16 Remicade (infliximab) Humira (adalimumab) Moderate to severe Crohn s disease Decreases steroid requirement Mucosal healing Healing of perianal disease Improvement of growth Bone health Prevention of post-operative recurrence Ulcerative colitis Treatment of moderate to severe disease Prevention of surgery

17 REACH Improved Growth with Infliximab Hyams, et al. Gastroenterology 2007;132:863-73

18 Anti-TNF α Therapy Remicade (infliximab) Intravenous infusion Loading dose 0, 2, 6 weeks Maintenance dose Every 8 weeks Can escalate if necessary Humira (adalimumab) SQ injection Loading dose Multiple injections wk 0,2 Maintenance dose Every 2 weeks Can escalate if necessary Need to pre-screen for tuberculosis No live vaccines

19 Anti-TNF Therapeutic Monitoring Measure trough level/antibodies against medicine Sub-therapeutic drug level Less likely to be effective Increase dose and/or decrease interval Antibodies against medication Less likely to be effective Can optimize dose Might have to switch agents Add immunomodulator

20 Vedolizumab (Entyvio) Gut specific anti-adhesion molecule 2014: Approved for adult Crohn and UC CHOP: ~30 patients have received Currently studying results

21 % Remission Remission (PCDAI < 10 or PUCAI <10) Baseline Week 6 Week 14 Week 22 n=21

22 Ustekinumab (Stelara ) for Active Crohn Disease Prevents binding of IL-12 and IL-23 to receptors Showed promise for adult CD patients with anti-tnf failure 09/2016: Approved for treatment of Crohn disease Side effect profile seems favorable Induction: Single IV weight-based dose Maintenance: 90 mg SQ q8 weeks Sandborn WJ et al. N Engl J Med 2012; 367:

23 Traditional Pediatric IBD Step-Up Algorithm Severe Surgery Moderate Mild Prednisone Steroids Budesonide Antibiotics Aminosalicylates Infliximab/ Adalimumab 6-MP/AZA Methotrexate Enteral Nutrition Probiotics

24 Does Early Use of Biological Therapy Improve Efficacy? Growth? Early Biologic therapy 6-MP/AZA/Methotrexate Steroids Late Surgery

25 Percent of patients (%) SONIC Trial Corticosteroid-Free Clinical Remission at Week p=0.025 p<0.001 p= /170 67/169 94/169 AZA + placebo IFX + placebo IFX+ AZA Colombel JF et al. N Eng J Med. 2010; 362:

26 Early Anti-TNF Therapy in Pediatric Crohn Disease Observational cohort of pediatric CD patients (inflammatory) Propensity score analysis matched patients on baseline characteristics in 68 triads Early anti-tnf (<3 mo) Early immunomodulator Neither Steroid-free Remission* at 1 Year p= p= % p= % 54.4% Early anti-tnf Higher remission rate Improved height z-score *Remission: PCDAI 10, steroid free, no surgery 20 0 Anti-TNF IM Neither Walters TD et al. Gastroenterology 2014; 146:383-91

27 Risk of Treating vs. Not Treating Risk of Treatment Risk of Disease Risk of Treatment

28 Long-Term Evolution of Pediatric Crohn Disease is Structural Damage Inflammatory Stricturing Penetrating Vernier-Massouille G et al. Gastroenterology 2008

29 What we (parents, patients and physicians) are most concerned about: Infection Lymphoma

30 Pediatric IBD Risk of Serious Infection: A Systematic Review Serious Infections per 10,000 Patient-Years P<0.001 P<0.001 P= Ped Anti-TNF Ped IM Adult Anti-TNF Ped Steroids Dulai PS et al. Clin Gastroenterol Hepatol 2014; 12:

31 Meta-Analysis: Biological Therapies and Risk of Infection 49 randomized, placebo controlled trials 14,590 participants For all studies, patients on biological therapy: 19% increased risk of all infections Serious infections not increased Higher risk of opportunistic infections (including Tb) For studies deemed low risk of bias Serious infections decreased in biologic exposed Bononvas S et al. Clin Gastroenterol Hepatol 2016; 14:

32 Vaccination Ensure that vaccines are up to date at time of diagnosis All non-live vaccines should be given Annual flu shot HPV vaccine Consider pneumococcal vaccine Avoid live vaccines if immunosuppressed MMR, Varicella, intranasal flu, others Try to confirm Varicella immunity prior

33 Risk versus Benefit of Biologics and Immune Suppressants in IBD Adapted from Siegel CA. Comprehensive approach to patient risk. Risk versus benefit of biologics and immune suppressants. In: Targan S, Shanahan F, Karp L, eds. Inflammatory Bowel Disease: Translating basic science into clinical practice

34 Risk of Developing NHL No immune suppression

35 Risk of Developing NHL -- Immunomodulator

36 Risk of Developing NHL Immunomodulator & Anti- TNF

37 Pediatric Develop Registry Largest prospective pediatric IBD safety cohort Patients assessed every 6 months, followed for 20 years 5,691 patients enrolled with > 20,000 PY of F/U Infliximab exposed do not have higher rate of malignancy than non-exposed Statistically significant slightly increased rate of malignancy in thiopurine exposed Hyams J et al. Gastroenterology 2017; epub ahead of press.

38 Less Risk of Malignancy with Biologic Monotherapy? Lichtenstein GR et al. Am J Gastroenterol 2014; 109:

39 Risk of Disease Often Greater than Risk of Treatment Risk of Treatment Risk of Disease

40 Thank you