Common Questions in Crohn s Disease Therapy Jean-Paul Achkar, MD, FACG Kenneth Rainin Chair for IBD Research Cleveland Clinic Case 23 yo male with 1 year history of diarrhea, abdominal pain and 15 pound weight loss. Exam notable for right sided abdominal tenderness Labs: WBC- 11.9; Hg- 9.1; MCV- 69; PLT- 610 Alb- 3.6; LFTs normal ESR & CRP- normal Stool studies negative for infection Copyright 2015 American College of Gastroenterology 1
Case CTe- 15 cm of TI inflammation Started on prednisone with good response Now returns for follow up What therapy now? Copyright 2015 American College of Gastroenterology 2
Questions in Maximizing Therapy for Crohn s What is the overall treatment goal? Single or combination treatment? Same approach for everyone? For how long? How can we maximize therapy? When do we switch therapies? Questions in Maximizing Therapy for Crohn s What is the overall treatment goal? Single or combination treatment? Same approach for everyone? For how long? How can we maximize therapy? When do we switch therapies? Copyright 2015 American College of Gastroenterology 3
Potential Treatment Goals in Crohn s Symptom improvement Avoid fistulizing/stricturing complications Minimize hospitalization Avoid/minimize surgery Mucosal healing Histologic healing Does achieving mucosal healing mean anything? YES! Copyright 2015 American College of Gastroenterology 4
Mucosal healing has been associated with: Decreased need for corticosteroids Decreased hospitalization rates Sustained clinical remission Decreased surgery rates Baert F, et al. Gastroenterology 2010;138:463-8 Copyright 2015 American College of Gastroenterology 5
Long-term Outcomes Following Mucosal Healing: Belgium Cohort study of 214 CD patients on IFX, followed for median of > 5.5 5 years Colonoscopy done before and at median of 6.7 months after starting IFX Complete MH 45.4%, Partial MH 22.4%, MH was associated with: Better disease free survival (P<0.001) Avoiding major abdominal surgery (14% vs 38%, P<0.05) Fewer hospitalizations (42% vs 59%, P<0.05) Schnitzler F, et al. Inflamm Bowel Dis 2010;15:1295-301 Questions in Maximizing Therapy for Crohn s What is the overall treatment goal? Single or combination treatment? Same approach for everyone? For how long? How can we maximize therapy? When do we switch therapies? Copyright 2015 American College of Gastroenterology 6
Top Down vs Step Up Study Patients 16-75 yo with: Dx of Crohn s within past 4 years and NO prior steroids, antimetabolites, or biologics CDAI > 200 for > 2 weeks On average CD was diagnosed less than 4 months before randomization in study participants Randomized to: Early combined immunosuppression Conventional treatment Primary analysis- Remission rates at weeks 26 & 52 D Haens, G. Lancet 2008;371:660-7 Early combined immunosuppression Infliximab- 5 mg/kg g at 0, 2 & 6 weeks AND Azathioprine- 2-2.5 mg/kg (MTX if intolerant) If symptoms persisted Methylprednisolone If responded but symptoms recurred: Infliximab first If still symptomatic Methylprednisolone D Haens G. Lancet 2008;371:660-7 Copyright 2015 American College of Gastroenterology 7
Conventional treatment Methylpred yp (32 mg) or budesonide (9 mg) with 10 week taper If symptoms persisted Methylprednisolone at 64 mg qd and azathioprine If responded but symptoms recurred: Steroids Azathioprine Infliximab D Haens G. Lancet 2008;371:660-7 CDAI < 150 & Off Steroids Copyright 2015 American College of Gastroenterology 8
Corticosteroid Use D Haens G. Lancet 2008;371:660-7 Mucosal Healing at 2 years 80 70 60 50 40 30 20 10 0 73.1 Early Immunosupp P=0.003 30.4 Conventional Tx D Haens G. Lancet 2008;371:660-7 Copyright 2015 American College of Gastroenterology 9
SONIC Trial Main Extension Visitsit Week 0* Week 2 Week 6 Week 10 Week 14 Week 18 Week 22 Week 26* Week 30 Week 38 Week 42 Week 46 Week 50 Week 54 Azathioprine 2.5 mg/kg + placebo infusions Randomization of patients Infliximab 5 mg/kg + placebo capsules Infliximab 5 mg/kg + Azathioprine 2.5 mg/kg Primary Endpoint (Corticosteroid-free Remission at Week 26) Infusions Secondary Endpoint (Week 50) * Endoscopy performed at Weeks 0 & 26 Steroid-Free Clinical Remission Wk 26 Patients with CRP 0.8 mg/dl & Lesions on Baseline Endoscopy (n=204) ion of patients (%) Proport 100 80 60 40 20 p<0.001 p<0.001 56.9 28.0 p=0.169 68.8 0 21/75 37/65 44/64 AZA+ placebo IFX + placebo IFX + AZA Copyright 2015 American College of Gastroenterology 10
Mucosal Healing at Week 26 100 ) Propo ortion of Patients (%) 80 60 40 20 0 p<0.001 p=0.023 p=0.055 43.9 30.1 16.5 18/109 28/93 47/107 AZA + placebo IFX + placebo IFX+ AZA Infliximab +/- Concomitant Immunomodulator in Pediatric Crohn s Grossi V. Clin Gastroenterol Hepatol 2015;13:1748-56 Copyright 2015 American College of Gastroenterology 11
In males, MTX was superior to thiopurine as concomitant treatment Grossi V. Clin Gastroenterol Hepatol 2015;13:1748-56 Immunogenicity: Week 30 Data from SONIC 15% Antibody Development (%) 15% 4 3 IFX Drug Level (ug/ml) P < 0.001 3.5 10% 5% 2 1 1.6 1% 0% IFX IFX + AZA 0 IFX IFX + AZA Copyright 2015 American College of Gastroenterology 12
Adalimumab 4 week Remission: CLASSIC vs GAIN 50% 40% 36% 30% 20% 10% 12% 7% 21% 0% CLASSIC (TNF naïve) Placebo GAIN (Prior IFX) ADA 160/80 mg Gastroenterology 2006;130:323-33 Ann Intern Med 2007;146:829-38 WELCOME: Certolizumab after secondary failure to infliximab 70% 60% 50% 40% 30% 20% 10% 0% 62% 48% PRECiSE 2 Wk 26 Remission 40% 29% WELCOME Wk 26 Response Schrebier S. NEJM 2007;357;239-250 Gastroenterology 2009;136(Suppl1): Abstract 143 Copyright 2015 American College of Gastroenterology 13
Questions in Maximizing Therapy for Crohn s What is the overall treatment goal? Single or combination treatment? Same approach for everyone? For how long? How can we maximize therapy? When do we switch therapies? Therapeutic options A B C D Immune response Early disease Late disease Copyright 2015 American College of Gastroenterology 14
PRECiSE 2: Response and Remission to Certolizumab pegol by Disease Duration Schreiber S. Am J Gastroenterol 2010;105:1584-82 CHARM: Response by Disease Duration Wk 26 Remission 50% 50% Wk 56 Remission 40% 30% 40% 30% 20% 10% 0% < 2 yrs 2 to 4 yrs > 5 yrs Placebo 20% 10% 0% < 2 yrs 2 to 4 yrs > 5 yrs Adalimumab Schreiber S. J Crohns Colitis 2013;7:213-21 Copyright 2015 American College of Gastroenterology 15
Early Predictors of Aggressive Disease Course Young age at diagnosis Need for steroid therapy at diagnosis Perianal disease Extensive small bowel disease Summary: Combination therapy Advantages: Better clinical response rates Less steroid use Higher mucosal healing rates Less immunogenicity/higher drug levels More likely to continue anti-tnf agent Which patients? Early disease Aggressive disease markers Copyright 2015 American College of Gastroenterology 16
Questions in Maximizing Therapy for Crohn s What is the overall treatment goal? Single or combination treatment? Same approach for everyone? For how long? How can we maximize therapy? When do we switch therapies? Withdrawal of Infliximab 1-year relapse rate = 44% Louis E et al. Gastroenterology 2012;142:63-70 Copyright 2015 American College of Gastroenterology 17
Multivariate Model for Relapse Factor HR P Ml Male 35 3.5 <0.001 001 No surgical resection 4.2 0.005 hscrp > 5 mg/l 2.7 0.005 Hg < 14.5 g/dl 5.5 0.001 WBC > 6.0 1.9 0.05 Fecal calprotectin > 300 3.1 0.01 Louis E et al. Gastroenterology 2012;142:63-70 Immunosuppressive Withdrawal IF FX change or D/C 80% 70% 60% 50% 40% 30% 20% 10% 0% 60% 55% + IS No IS Van Assche G. Gastroenterology 2008;134:1861-8 Copyright 2015 American College of Gastroenterology 18
Predictors of infliximab failure after azathioprine withdrawal Retrospective observational study 48 patients who had received IFX + AZA for > 6 months Predictor HR P Time of comb tx < 811 days 7.46 0.01 CRP > 5 mg/l 4.79 0.008 AZA D/Ced PLT > 298 4.75 0.02 Oussalah A. Am J Gastroenterol 2010;105:1142-9 Questions in Maximizing Therapy for Crohn s What is the overall treatment goal? Single or combination treatment? Same approach for everyone? For how long? How can we maximize therapy? When do we switch therapies? Copyright 2015 American College of Gastroenterology 19
Back to our case He is started on adalimumab at 40 mg q 2 weeks and azathioprine at 50 mg qd 6 months later- notes marked improvement in symptoms ( best I ve felt in 2 years ) but still has mild diarrhea and intermittent abdominal pain Colonoscopy shows improvement but there are still scattered superficial ulcers in terminal ileum. Utility of drug levels in adjusting therapy Copyright 2015 American College of Gastroenterology 20
6-MP Metabolism 6-Methyl Methyl-Mercaptopurine Mercaptopurine (6-MMP) TPMT Azathioprine 6-MP HPRT Thioinosinic Acid 6-Thioguanine nucleotides (6-TGN) XO 6-Thiouric Acid Meta-Analysis: Correlation of 6-TGN threshold and remission Osterman MT. Gastroenterology 2006;130:1047-53 Copyright 2015 American College of Gastroenterology 21
Non-Response to 6-MP Study of 51 IBD patients failing therapy with 6-MP or AZA 6-MP metabolite levels measured before and after dose escalation: 14 patients (27%) responded clinically 37 patients had no clinical benefit Effect of Dose Escalation on 6-TGN Levels 900 P = 0.03 8 RBC) level (pmols/8 x 10 8 6-TGN 800 700 600 500 400 300 200 100 0 Time 0 Time 1 Time 0 Time 1 Non-Responders Responders Dubinsky et al. Gastroenterology 2002;112:904. Copyright 2015 American College of Gastroenterology 22
Metabolite Monitoring in Non-Responders Identify reasons for non-response: 6-TGN 6-MMP Inadequate dose Non-adherence 0 6-MMP shunting Drug resistance Utility of Infliximab Levels & Antibodies Medical records of 155 IBD pts who had antibodies & levels drawn in clinical practice ATIs (23%) change to another anti-tnf led to complete/partial response in 92% Low infliximab (44%) dose escalation led to complete/partial e/p response se in 86% Therapeutic infliximab (33%) no evidence of active inflammation in 62% Afif W, et al. Am J Gastroenterol 2010;105:1133-40 Copyright 2015 American College of Gastroenterology 23
Drug and antibody levels in guiding inteventions after loss of response Study of 247 patients who developed loss of response to infliximab or adalimumab Adalimumab: Trough drug level > 4.5 mcg/ml: 90% specificity for no response to dose intensification Predictive of response to either NO change in tx OR to change out-of-class tx Antibody level > 4 mcg/ml: 90% specificity for failure to respond to dose intensification Yanai H. Clin Gastroenterol Hepatol 2015;13:522-530 Drug and antibody levels in guiding inteventions after loss of response Infliximab: Trough drug level > 3.8 mcg/ml: 90% specificity for no response to dose intensification Predictive of response to either NO change in tx OR to change out-of-class tx Antibody level > 9 mcg/ml: 90% specificity for failure to respond to dose intensification Shorter duration of response after regained response Yanai H. Clin Gastroenterol Hepatol 2015;13:522-530 Copyright 2015 American College of Gastroenterology 24
Drug level correlates with mucosal healing Ungar B. Clin Gastroenterol Hepatol 2015; in press Effect of Antibody Positivity on Anti-TNF response: Meta-Analysis Garces S. Ann Rheum Dis 2013;72:1947-55 Copyright 2015 American College of Gastroenterology 25
Applying Drug/Ab Levels in loss of or non-response Low drug level Good drug level Low drug level No/low Ab level No/low Ab level High Ab level Increase anti- TNF dose?active inflammation Anti-TNF switch YES NO Out of class switch Look for non- IBD causes Putting it all together Copyright 2015 American College of Gastroenterology 26
Treat to Target: A Potential Approach In patients with aggressive disease start anti-tnfs + immunosuppressive early in disease course: Best effects with disease duration < 2 years Mucosal healing for CD of 44% at 26 weeks (SONIC) and 73% at 2 years (Top-Down) Assess for mucosal healing within 6 months of medication start or medication adjustment: Ed Endoscopy?surrogate markers Use drug levels & different classes of medications to guide decisions for medical tx changes Is there evidence to support such an approach? Copyright 2015 American College of Gastroenterology 27
35% 30% EXTEND: Deep remission rates based on duration of disease 33% 33% 25% 20% 15% 10% 5% 0% 20% 14% 16% 13% 10% 7% 0 0 0 0 < 2 yrs 2-5 yrs > 5 yrs < 2 yrs 2-5 yrs > 5 yrs Week 12 Week 52 ADA Placebo Treat to Target Approach Retrospective review of 67 CD patients: Baseline endoscopy with ulcers in any GI segment AND Had at least 2 F/U endoscopies during study period Evaluated impact of medical tx changes on: Mucosal healing- absence of any ulcers Endoscopic improvement- downgrading of deep ulcers to superficial ulcers OR disappearance of superficial ulcers Bouguen G. Clin Gastroenterol Hepatol 2014;12:978-85 Copyright 2015 American College of Gastroenterology 28
Median F/U duration 62 wks (44-79) # of F/U endoscopies: 2 3 4 Follow-Up 67 (100%) 21 (31%) 6 (9%) Median time between 1 st 2 procedures 24 wks (17-38) Cumulative Probability of MH/Improvement: 24 weeks 56 weeks Changes in medical therapy: Anti-TNF started Anti-TNF dose optimized Switch to another anti-tnf Immunosuppressive started Switch to ustekinumab 13%/15% 45%/54% N 37 17 9 35 7 Bouguen G. Clin Gastroenterol Hepatol 2014;12:978-85 Multivariate Analysis for Endoscopic Outcomes Endoscopic Outcome OR (95% CI) Mucosal Healing: Adjustment of medical therapy 359(14110 3.59 (1.41-10.40) 40) Endoscopic improvement: Adjustment of medical therapy Endo procedures within 26 wks 2.08 (1.04-4.50) 1.95 (1.02-3.81) Discrepancy between clinical symptoms & endo inflammation: 41% had symptoms despite mucosal healing (all w/ nl CRP) 19% w/ significant endoscopic lesions had no clinical symptoms Bouguen G. Clin Gastroenterol Hepatol 2014;12:978-85 Copyright 2015 American College of Gastroenterology 29
Cost Effectiveness Analysis of Mucosal Healing as an Endpoint Clinical response (CR) arm- IFX dose escalation in patients not in clinical remission Mucosal healing (MH) arm- IFX dose escalation in patients without mucosal healing After 2 years, MH was more effective but more expensive- ICER $49,278 per QALY gained Ananthakrishnan AN, Inflamm Bowel Dis 2013;19:37-44 Decision Analysis Hypothetical 100,000 pt cohort in each arm CR arm vs MH arm: Dose escalations: 51,479 vs 56,686 (+5,207) Hospitalizations: 16,679 vs 12,844 (-3,835) Surgeries: 3,851 vs 2,881 (-970) Number needed to treat: Prevent 1 hospitalization NNT = 27 Prevent 1 surgery NNT = 106 Ananthakrishnan AN, Inflamm Bowel Dis 2013;19:37-44 Copyright 2015 American College of Gastroenterology 30
Summary Combination therapy is better than monotherapy: Clinical response/remission; less steroid use Mucosal healing Reduced immunogenicity Mucosal healing: Can be achieved in anywhere from 30-70% of patients Better outcomes in early disease Is associated with better long term outcomes With drug monitoring tests and new classes of drugs, there will be increasing options to tailor medical therapy treat to target concept Copyright 2015 American College of Gastroenterology 31