NASPGHAN VIRTUAL IBD CASE STUDY Evidence and Art: Anti TNF Antibody - PDF document

9/17/2013 NASPGHAN VIRTUAL IBD CASE STUDY Evidence and Art: Anti ‐ TNF α Antibody Therapy for Pediatric Crohn’s Disease Moderators • Brendan Boyle, MD • Ted Denson, MD • Neera Gupta, MD • Anne Griffiths, MD • Subra Kugathasan, MD • David Mack, MD • James Markowitz, MD • Maria Oliva ‐ Hemker, MD • Anthony Otley, MD • Joel Rosh, MD • Cary Sauer, MD • Michael Stephens, MD • Tom Walters, MD Case • B.A. is a 14 year old boy who presents with 6 month history of weight loss (12 pounds), intermittent abdominal pain and diarrhea without blood, arthralgias, and for the past 2 weeks fever daily to 38.5 o C, and erythema nodosum • Exam normal with exception of tender nodules on anterior shins, mild clubbing, pallor. Abdomen not tender, no perirectal disease • Weight 39 kg (<5%), Height 153 cm (10%), Tanner 2 1

9/17/2013 Case • Seen initially in rheumatology clinic where labs reveal: Hb 9.9 g/dl, CRP 14.35 (nl <0.5 mg/dl), ESR 52 mm/hr, albumin 2.9 g/dl, vitamin D 13 ng/ml • Referred to GI: EGD: normal grossly, biopsies reveal patchy inflammation with granuloma in stomach and duodenum Ileocolonoscopy: extensive ulceration of terminal ileum and right colon, grossly normal transverse colon, patchy inflammation in rectosigmoid. Biopsies confirm chronic inflammation, rare granuloma MRE: extensive distal ileal disease, no stricture or abscess Case – Terminal Ileum • Show endoscopic photos Case: MRI Axial contrast enhanced image. Diffuse enhancement of terminal ileum 2

9/17/2013 Case: Summary • 14 year old, extensive ileal and right colonic disease • Tanner II, height <5%, wt 10% • Is there any further information you want before deciding on this patient’s therapy? Potential Further Evaluation (Vote): • A. I don’t need any further testing • B. Antibodies to microbial antigens (ASCA, OmpC, CBir, etc.) • C. Video Capsule Endoscopy • D. Both B andC Results of Additional Tests • Serology shows: ASCA IgA 61 (<8.5), ASCA IgG 18.8 (<17.8), anti ‐ OMP C IgA 8.9 (<10.9), anti ‐ Cbir1 IgG 21.5 (<78.4) • Video Capsule – not done 3

9/17/2013 Antibody Sum and Disease Behavior P trend < 0.0001 NPNS 100 100 Frequency of Disease Behavior % IP S P trend < 0.0001 Surgery 80 * 9.5 * 60 * 6.1 5.0 * * 40 2.2 4.2 * * 1.0 1.7 * 20 1.0 0 0 1 2 3 * Odds Ratio N=199 N=262 N=57 N=194 Number of Immune Responses Dubinsky MC et al CGH 2008;6:1105 Case 1: Therapeutic Options (Vote) • Option 1: Prednisone followed by 5 ‐ ASA • Option 2:Prednisone followed by 6 ‐ MP/Aza • Option 3: Prednisone followed by methotrexate • Option 4: Exclusive enteral nutrition followed by IM • Option 5: Anti ‐ TNF α monotherapy • Option 6: Anti ‐ TNF α plus thiopurine • Option 7: Anti ‐ TNF α plus methotrexate • Option 8: Intensive helminth therapy Natural History (Vote) • Which of the following therapies do you believe is most likely to alter the natural history of Crohn’s disease A. Immunomodulators B. Anti ‐ TNF α C. Neither 4

9/17/2013 Which of these therapies has greatest risk: (Vote) • A. Biologics • B. Thiopurines • C. Methotrexate • D. Biologics and thiopurine combination • E. Biologics and methotrexate combination If you had felt strongly about starting anti ‐ TNF α and a concomitant IM which one: (VOTE) • A. Thiopurine • B. Methotrexate Effect of Co ‐ Treatment with Immunomodulators on Disease Outcome During Scheduled Maintenance Therapy With Infliximab Sokol et al. Gut 2010;59:1363 5

9/17/2013 Effect of Co ‐ Treatment with Immunomodulators on Disease Outcome During Scheduled Maintenance Therapy With Infliximab Sokol et al. Gut 2010;59:1363 Case • Started on 40 mg prednisone while prior approval obtained for infliximab. • After discussion with the family of potential benefits and risks of anti ‐ TNF α and IM therapy they feel most comfortable starting infliximab monotherapy. Started 1 week after diagnosis • Weight 39kg. Given 200 mg at 0, 2, and 6 weeks. Started on Fe, Vit D. Prednisone tapered over next 5 weeks • At 8 week visit is feeling much better, PCDAI 5 Case • Seen at 6 months and patient states that he is having mild abdominal pain and stools are looser for the week or two before his next infusion. • ESR 25, CRP 2.0 (<0.8), Hb 13, albumin 3.6 g/dl 6

9/17/2013 At this point I would (Vote): • A. Empirically increase the dose of infliximab to 10mg/kg/dose • B. Empirically decrease the interval between infusions to 6 weeks but leave the dose at 5 mg/kg • C. Check a trough infliximab level along with antibody to infliximab (ATI) • D. Start a brief course of prednisone and leave infliximab schedule the same Father of patient is hedge fund manager and $ is no object • Infliximab level and ATI are obtained: • Infliximab level 0 ug/ml, ATI 0 U/ml (ELISA test) • So minimal circulating infliximab and no evidence of antibody. What would you do? • Increase the dose to 10 mg/kg and keep at every 8 weeks • Decrease the interval to 6 weeks and leave at 5 mg/kg • Something in between 7

9/17/2013 Case • Infliximab dose increased to 10 mg/kg and interval kept at 8 weeks • Patient does well for 1 ½ years Case • At next visit he comes in stating that his abdominal pain has increased greatly, he is sleeping poorly, he is having 5 ‐ 6 stools per day and feels tired all the time, weight down 2 lbs • Now 16 years old, weight and height are both at 25%, Hb 13, ESR 20, albumin 3.6 g/dl, CRP 1.4 (nl <0.8) At this point I would (Vote): • A. Get infliximab level and antibody to infliximab* • B. Empirically decrease intervals between infusions to 6 weeks • C. Start a brief course of prednisone • D. Repeat evaluation including ileocolonoscopy and MRE *Father now under investigation by SEC, bank accounts frozen, no money. States they cannot afford to do the testing 8

9/17/2013 Repeat Evaluation Performed • Mild terminal ileal inflammation on biopsy only, normal colon • Repeat MRE shows minimal enhancement of terminal ileum • Patient and family state that terrible stress secondary to father’s indictment, harassment in school • Psychosocial support, patient improves Case – Two Years Later • Father exonerated of all wrong doing, making $12 million again, family happy • But, 17 year old patient now states he is having increased abdominal pain, diarrhea, weight loss, fevers. Terrible stress with college applications and broke up with girlfriend • ESR 42, albumin 3.2, CRP 7 (nl <0.8) At this point I would (VOTE): • A. Get infliximab level and antibody to infliximab • B. Empirically increase infliximab dose to 10 mg/kg every 4 weeks • B. Empirically switch to adalimumab • C. Empirically switch to certolizumab • D. Start a brief course of prednisone • E. Repeat evaluation including ileocolonoscopy and MRE 9

9/17/2013 Case Undetectable drug, low titer antibody at trough At this point I would (Vote): • A. Switch to adalimumab (in class) • B. Switch to natalizumab (out of class) • C. Perform ileocecal resection • D. Infliximab 10 mg/kg every 4 weeks and add IM What Does a Low titer Antibody Level Mean? • Vande Casteele et al. Antibody response to infliximab and its impact on pharmacokinetics can be transient. Am J Gastro 2013;108:962 • Use of novel mobility shift assay that detects both infliximab and antibody whereas ELISA could only detect antibody in the absence of drug 10

9/17/2013 Transient vs. Sustained Antibodies to Infliximab Vande Casteele et al. Am J Gastro 2013;108:962 Patients with sustained ATI more often have to stop IFX owing to LOR or hypersensitivity reaction Time to discontinuation owing to LOR or hypersensitivity is shorter in those with sustained versus transient antibodies Vande Casteele et al. Am J Gastro 2013;108:962 Case – Can I Recapture Response at This point? • Patient started on methotrexate • Infliximab dose 10 mg/kg, interval every 4 weeks • Patient clinically improves, and 3 months later infliximab level 16, ATI 0 (ELISA) by another lab that does the old assay • Goes off to the University of Connecticut and and does well for his first 2 years. Life is great. 11

9/17/2013 What Assay Am I Using? • Can I measure drug and antibody to drug simultaneously, or does presence of circulating drug preclude such measurement? With ELISA the presence of circulating drug precludes measuring antibody levels Ordas et al. Clin Gastroenterol Hepatol 2012;10:1079 Mobility Shift Assay Ordas et al. Clin Gastroenterol Hepatol 2012;10:1079 12

9/17/2013 Case ‐ Patient decides to spend junior year in college in Botswana, and asks… • Can I switch to adalimumab? I don’t think I can find an infusion center in Botswana. • What is my likelihood of doing well? • Can I ever go back to infliximab when I come home? SWITCH study Van Assche et al. Gut 2012;61:229 Overview of Outcomes Following Elective Switch From Infliximab to Adalimumab 2% 14% 19% Stable Stable 53% Early term 28% Early term 84% Dose escal Dose escal Group A. Adalimumab Group B. Infliximab Van Assche et al. Gut 2012;61:229 13