What Do I Do When Anti-TNF Therapy Is Not Working Anymore? Fadi Hamid, M.D. Saint Luke s GI Specialists Disclosures No financial relationships to disclose. 1
Learning Objectives Case 24M with ileocolonic Crohn s disease on adalimumab 40 mg every other week who achieved symptomatic and endoscopic remission but now has increased signs and symptoms with abdominal pain, anemia, and loose stools. 2
Does Patient Have Active Disease? bile salt diarrhea intestinal infection small intestinal bacterial overgrowth bypass from a fistula lactose intolerance irritable bowel syndrome food intolerance intestinal obstruction or a stricture medication-related diarrhea (like 5-ASA) 5 Workup Stool studies including C diff PCR CRP Fecal calprotectin, stool lactoferrin Colonoscopy CTE or MRE 3
Workup Negative C diff PCR CRP 28 (Normal < 10) Fecal calprotectin 204 (normal < 120) CTE showed active ileo-colonic Crohn s disease without fistulas, strictures or intestinal obstruction Colonoscopy- SES-CD 11 Endoscopic Mayo score for UC 8 4
What is Next? 1. Course of corticosteroids and continue same dose of adalimumab 2. Increase dose of adalimumab 3. Add azathioprine 2.5 mg/kg daily 4. Switch therapy 5. Surgery referral 9 Why Is Immunogenicity Important? Trough levels of anti-tnf -Are significantly lower in patients losing response to anti-tnf -Are significantly lower in patients without mucosal healing Antibodies against anti-tnf -Are more frequent in patients losing response to anti-tnf -Are associated with low trough level of anti-tnf -Are associated with infusion reactions -May fluctuate over time 10 5
Why Do Drug Levels Vary Between Patients? Anti-drug antibodies causing clearance Concomitant IM therapy High concentrations of TNF causing clearance Drug loss through inflamed colonic mucosa (protein losing enteropathy) Male gender- increased drug loss Body size 11 What to Do if Anti-TNF Therapy Is Not Working? IBD flare Inflammation present No ADA? Adequate drug level Yes Switch class No Increase dose Yes Switch to another anti-tnf or add IM 12 6
Available Biologic Therapy Anti-TNF Infliximab Adalimumab Certolizumab (CD) Golimumab (UC) Anti-integrin Natalizumab: α4β7 and α4β1 (CD) Vedolizumab: α4β7 Anti-IL12/23 Ustekinumab (CD) JAK Inhibition Tofacitinib (UC) 13 Switching to Other Biologic Drugs Studies assessing switch from infliximab to injectable TNF in secondary non-responders only - GAIN (adalimumab) - WELCOME (certolizumab) - Did not account for therapeutic drug monitoring No randomized trials looking at switching from injectable to intravenous anti-tnf agent. However anecdotally switching from injectable (underdosed) to intravenous (infliximab) can be helpful, particularly in severe colonic disease 14 7
Adalimumab Induction Therapy For Crohn Disease Previously Treated With Infliximab Sandborn W et al. Annals of Internal Medicine Volume 146 Number 1 Certolizumab Pegol in Patients With Moderate to Severe Crohn s Disease and Secondary Failure to Infliximab Sandborn W et al. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2010;8:688 695 8
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GEMINI 3: VDZ Induction in Crohn s Patients Who Had Failed Anti-TNF Agents 315 moderate to severe CD who had failed anti-tnf, 101 TNF naive, randomized 1:1 to PBO or VDZ 300 mg IV weeks 0, 2, and 6 Missed primary endpoint of remission at week 6, but met same endpoint at week 10 GEMINI 3: VDZ Induction in Crohn s Patients Who Had Failed Anti-TNF Agents Sands BE et al, Gastroenterology 2014;147:618-27. VICTORY Consortium: Real World Effectiveness of Vedolizumab Crohn s 7 academic medical centers in US 212 mod-severe CD treated with VDZ between 5/14 and 12/15, 90% previous anti-tnf exposure 12 month cumulative rates -Remission, 35% -Mucosal healing, 63% -Deep remission, 26% Prior anti-tnf exposure, severe disease, perianal disease and smoking activity impacted remission rates Dulai PS et al, Am J Gastroenterol 2016;111:1147-55. 10
Feagan/Sandborn et al, N Engl J Med 2016;375:1946-60. Sandborn et al, NEJM May 2017 11
Costello et al, Presented at DDW on 9th of May 2017, Abstract no 1078 11/1/18 Thank You 24 12