Management of Refractory Crohn s Disease

Transcription

1 Management of Refractory Crohn s David T. Rubin, MD, FACG, FASGE Joseph B. Kirsner Professor of Medicine Chief, Section of Gastroenterology, Hepatology and Nutrition Disclosures Consultant and Grant Support Abbvie Amgen Cellgene Janssen Pfizer Prometheus Takeda UCB Board Membership/Other ACG Board of Trustees VP, Cornerstones Health, Inc (non-profit medical education organization) Page 1 of 18

2 Learning Objectives Incorporate an approach to the patient not responding to therapy Develop a prudent approach to the patient losing response to therapy Understand the use of objective disease markers to improve patient compliance with therapeutic recommendations Who is the Refractory IBD Patient? 1. The patient not responding to therapy 2. The patient who loses response to therapy 3. The patient you don t like 4. The patient who refuses your therapeutic recommendations Page 2 of 18

3 1. The Patient Not Responding to Therapy Primary Non-response What is Primary Non-Response? Based on type of disease and scenario? Hospitalized severe ulcerative colitis: No improvement after 3 days of IV steroids Crohn s disease after surgery: Rapid recurrence and repeat surgery despite appropriate post-op meds After multiple therapies sequentially? Page 3 of 18

4 Based on therapy received? What is Primary Non-Response? 5-ASA Maximum dosing orally and rectally 2-4 weeks no improvement Steroids Budesonide 9 mg 2 weeks no improvement Oral prednisone 40 mg 2 weeks no improvement Methotrexate/Thiopurine 25 mg SC/w no improvement after 4-6 weeks Weight based dosing of thiopurine or 6-TGn based dosing after 6-12 weeks Anti-TNF After loading doses and first maintenance dose May include early dose escalation May be a difference between SC and IV anti-tnf therapies Anti-Integrin (mostly vedolizumab) After loading and first maintenance dose Primary Non-Response Is this a mechanism failure? Biological mechanism (eg not TNF-driven) Not inflammation (eg scar tissue, IBS, infection) Infection? Or a dose failure? Underdosage Overdosage (?) Exposure issues (eg leakage of protein in stool) Page 4 of 18

5 Approach to Primary Non-Response Use objective measures of disease activity Rule out strictures, infection Consider drug intolerance (esp 5-ASA) Confirm adherence Consider switch from SC to IV anti-tnf Where is the drug going? Understand who is at risk for needing more Low albumin 1 Males, high BMI etc 1 Role of therapeutic drug monitoring 1 Ordas I, et al. Clin Pharmacol Ther. 2012;91(4): Ding NS, et al. Aliment Pharmacol Ther. 2016;43: Pitfalls of Primary Non-Response Giving up too early More often, waiting too long Not engaging surgery early (or even FIRST!) Inappropriate dosing: usually underdosing Inability to assess pk Page 5 of 18

6 The Patient Failing Everything Surgery Permanent ileostomy J pouch Temporary loop ileostomy Disappointing results of loop ileostomies and rectal/perianal disease 1 Bowel rest (CD) and TPN Clinical trials (usually don t qualify) Off label options: Novel available therapies (anti-il12/23; tofacitinib) Tacrolimus Mycophenolate Anti-MAP therapy (?) 1 Lopez J, et al. Inflamm Bowel Dis. 2014;20(7): The Patient Who Loses Response to Therapy Secondary Non-response Page 6 of 18

7 0 0 0 David T. Rubin, MD, FACG, FASGE The Patient Who Loses Response to Therapy Change in dose (by you) Change in delivery Change in physiology Does disease change over time? Intentional nonadherence Episodic dosing strategy Denial Fear of therapy Patients don t respond to medications that they don t take! Unintentional nonadherence Can t afford medication Inconvenient dosing regimen Loss of Response to anti-tnf Therapy is Common Moderate to Severely Active IBD Most Failing Immune modulators Long Duration of Disease ACCENT I 1 Infliximab CDAI 70 & 25% reduction 5mg/kg q8 54 weeks CHARM 2 Adalimumab CDAI 70 40mg eow 56 weeks PRECiSE 2&3 3,4 Cert pegol CDAI 100 & HBI 400mg q4 80 weeks 100% 100% 100% 52% 38% 54% 43% 63% 54%* 44%* 0% % % Months Months Months IFX ADA certolizumab pegol Placebo Placebo certolizumab pegol open label Placebo 1 Hanauer SB, et al. Lancet. 2002;359(9317): Colombel JR, et al. Gastroenterology. 2007;132(1): Schreiber S, et al. Gut. 2006; 55(Suppl V):A Lichtenstein G, et al. Gastroenterology. 2007;132(Suppl 2):A502 (Abstract T1264). Page 7 of 18

8 Patients at Risk for Anti-Drug Antibodies The patient receiving episodic therapy Intentional Unintentional: break in therapy due to coverage issues or complication Pseudo-episodic therapy Sub-therapeutic serum drug levels 1 The patient with drug clearance between doses The patient who developed anti-drug antibodies previously 2 The patient with high ASCA titers (?) 1 Vermeire S, et al. Gut. 2007;56(9): Rubin DT, et al. ACG Why Is Combination Therapy More Effective? True for both CD (SONIC) and UC (SUCCESS) with infliximab 1,2 Multiple mechanisms of disease control Reduction in anti-drug antibodies Elevation of serum drug levels (greater exposure) Other mechanisms/unknown 1 Colombel JF, et al. N Engl J Med. 2010;362(15): Panaccione R, et al. Gastroenterology. 2014;146(2): Page 8 of 18

9 What s the Optimal Dose of Concomitant Therapy? 6TGN level pmol/8 x 10 8 RBC Thiopurine 1 : 6-TGn 125 pmol/8 x 10 8 RBCs Correlation Between 6-TGN and IFX Concentrations 193 ATI NEG 117 ATI POS Methotrexate 2 : 15 mg/w Maintenance of Remission by MTX Dose 1 Yarur A, et al. Clin Gastroenterol Hepatol. 2015;S (14): Colman RJ, Rubin DT. Crohns Colitis. 2015;9(4): Early Assessment of Drug Levels Correlates with Longer Term Response Crohn s disease: detectable week 14 infliximab trough levels are associated with week 54 efficacy outcomes 1 adalimumab trough levels predict sustained clinical response 2 Ulcerative colitis: higher infliximab concentration at week 8 associated with higher weeks 30 and 54 clinical remission rates 3 rapid clearance of infliximab leads to ATI, non-response 4 Stool levels of infliximab correlate with lack of response 5 1 Singh N, et al. Inflamm Bowel Dis. 2014; 20(10): Karmiris K, et al. Gastroenterology. 2009; 137: Adedokun OJ, et al. Gastroenterology. 2014; 147(6): Kevans D, et al. DDW, Brandse JF, et al. Gastroenterology. 2015;149(2): Page 9 of 18

10 Clinical Assessment of Disease Control Routine inquiry regarding stability of disease control (stable maintenance between doses) Strict adherence to maintenance regimen Ongoing laboratory assessment of clinical stability Increasing utilization of surrogate markers of inflammatory activity (fecal calprotectin) Trough Levels of Drug Correlate with Clinical Response Higher levels assoc with mucosal healing with infliximab 1, adalimumab 2, certolizumab pegol 3 Associated with response, remission 4 But optimal levels are in a range 5 1 Hanauer SB, Lancet. 2002;359(9317): Roblin X, et al. Clin Gastroenterol Hepatol. 2014;12(1): Colombel JF, et al. Clin Gastroenterol Hepatol. 2013;13(6): Seow CH, et al. Gut. 2010;59(1): Chiu YL, et al. Inflamm Bowel Dis. 2013;19(6): Page 10 of 18

11 Dose Optimization Increases Probability of Remaining on Infliximab Up to 5 years Retrospective cohort of patients in clinical remission, single physician practice Infliximab dose optimisation to trough concentrations 5 10 µg/ml (n=48) No infliximab dose optimisation (n=78) 100 Probability on infliximab p= Optimised Not optimised Weeks on infliximab Vaughn BP, et al. Inflamm Bowel Dis. 2014;20(11): Optimized Infliximab Levels (3-7 mcg/ml) Associated with Stable Maintenance (TAXIT) Clinically based (CB) and trough level based (LB) groups 100 p= Patients (%) (N=122) (N=126) CB group LB group Clinical remission Relapse-free survival LogRank p= Breslow p= CB Group LB Group Maintenance phase (weeks) TAXIT: Prospective controlled Trough level Adapted infliximab Treatment Vande Casteele N, et al. Gastroenterology. 2015;148(7): Page 11 of 18

12 Approach to the IBD Patient Losing Response to Anti-TNF Therapy Using Therapeutic Drug Monitoring Measurement of anti-tnf level and anti-drug antibodies Undetectable or low anti-tnf level and (-) ADA High anti-tnf level and (-) or (+) ADA Undetectable or low anti-tnf level and (+) ADA Increase anti-tnf dose or decrease dose interval Swap to another drug class High ADA level Low ADA level Cycle anti-tnf or swap drug class Transient? Dose optimization and consider adding IMM No response Yarur A and Rubin DT. Inflam Bowel Dis. 2015;21(7): The Patient You Don t Like Page 12 of 18

13 Understanding the Hateful Patient Understand countertransference Emotional reactions to a patient due to the clinician s conflict with them (on any level) Like the mother who occasionally can hate her crying baby Four classes of patients Dependent clingers Entitled demanders Manipulative help-rejecters Self-destructive deniers Groves JE. N Engl J Med. 1987;298(16): Strategies for Managing the Hateful Patient Setting limits Setting boundaries Getting others involved Time follow-up and disease assessment Getting a second opinion Ceasing care relationship Adapted from Groves JE. N Engl J Med. 1987;298(16): Page 13 of 18

14 4. The Patient Refusing Therapy Why Do Patients Refuse Therapeutic Recommendations? Fear of adverse events from therapy Misunderstanding of therapeutic goals or intent of the therapy Difference in goals of therapy between patient and provider Misinformation about why this therapy was recommended Lack of trust with the physician/health care provider Page 14 of 18

15 Refusal of Therapy Refusal is the right of the competent and autonomous patient 1. Tension/breakdown of doctor-patient relationship can occur when the physician believes the recommendation is based on solid evidence and a strong benefit:risk profile 2. Tension/breakdown of DPR when ego and threat to physician authority get in the way of respect for patient autonomy If the physician s interests are more important than the patient s, this is ethically unacceptable, and possibly morally so What is Unique About IBD When It Comes to Patients Refusing Therapies? No cure Unknown cause Perception that it must be related to diet or stress, both of which affect bowel symptoms Dietary adjustments can improve symptoms Lots of miracle cures on the Internet Page 15 of 18

16 The Power of Anecdote Patients cling to anecdotes of success for unproven or insufficiently studied therapies Internet explosion Word Cloud from Internet Sites about Anti-TNF Biologic Therapy Page 16 of 18

17 The Power of Anecdote Patients cling to anecdotes of success for unproven or insufficiently studied therapies Internet explosion Patients cling to anecdotes of adverse events for available/fda-approved studies Complicated further by the fact that FDA approved therapies have substantial and mandated safety programs and publicly available data Direct to consumer advertising requires that half the air time is spent on safety issues Getting Your Patient on Effective Therapy Shared Decision Making What is the risk of untreated or ineffectively treated disease Agreement in goals (improved quality of life, avoidance of surgery and hospitalization, etc) Negotiate trial of therapy and plan of follow-up Perception of risk changes with efficacy Individualize risk Use of objective disease monitoring tools to assess and to communicate disease activity Negotiated follow-up (short-term) to reassess disease activity OBJECTIVELY Rubin DT, Krugliak Cleveland N. Am J Gastroenterol. 2015;110(9): Page 17 of 18

18 David T. Rubin, MD, FACG, FASGE Summary: Management of Refractory Crohn s Disease The primary non-responder: Confirm diagnosis- look for overlaps Don t underdose! Surgery The secondary loss of responder: Why is this happening? Understand therapeutic drug monitoring Know your options: pk adjustment vs. changing therapies The patient refusing therapy: Work through objective disease monitoring strategies Individualize treatment options and prognostic explanations Page 18 of 18