Optimizing Immunomodulators and Biologics i in Inflammatory Bowel Disease Sunanda Kane, MD, MSPH, FACG Professor of Medicine Division of Gastroenterology and Hepatology Mayo Clinic Rochester, Minnesota, USA Overview Disease characteristics to consider Disease characteristics to consider Thiopurine metabolism Issues with biologics October 2012 1
mulative Probability (% %) Cu 100 90 80 70 60 50 40 30 20 10 Long-term Evolution of Disease Behavior in CD Inflammatory Penetrating Stricturing 0 0 12 24 36 48 60 72 84 96 108120 132144 156168 180192 204216 228240 Months Patients at risk: N = 2002 552 229 95 37 Cosnes J et al. Inflamm Bowel Dis. 2002;8:244. Predictors of Risk for Progressive/Aggressive Crohn s Disease Young age at onset Fistulizing, perianal disease Early need for steroids Deep ulcerations High serologic/genetic g (NOD2) titers Smoking October 2012 2
Predictors of Rapid Progression to Surgery Sands BE. Am. J. Gastroenterol. 2003; 98: 2712-8. Treating IBD: Goals of Management Confirm accurate diagnosis Induce remission i Remission in clinical trials vs clinical practice Maintain remission 95% of patients require maintenance therapies Need effective and safe long-term therapies Enhance quality of life Avoid adverse events Complications of the disease, including surgery Safety issues associated with therapy October 2012 3
Advantages Step Up Management Patients attain remission with less toxic therapies Potentially more toxic therapies reserved for more severe or refractory disease Minimizes risk of adverse events Cost sparing (short-term?) Disadvantages Patients have to "earn" most effective treatments - decrease in quality-of-life before patients obtain optimal therapy Likelihood of surgery is high Disease is not modified Metabolism of AZA/6-MP 101 XO 6-thiouric acid AZA 6-MP HPRT 6-TGNs TPMT 6-MMP October 2012 4
Thiopurine Metabolism 202 Dewit O et al, Eur J Clin Invest 2010;40(11): 1037-47. TPMT Considerations Explains only early leukopenia Still need monthly CBC to avoid delayed leukopenia Genotype vs. phenotype? Normal TPMT: 2-2.5 mg/kg AZA, 1-1.5 mg/kg 6MP Intermediate/heterozygous: 1-1.25 mg/kg AZA, 0.5-0.75 mg/kg 6MP Universal TPMT testing appears cost-effective in several decision analysis models October 2012 5
TPMT Activity in 407 New Zealand Patients Wild type Homozygous mutation Heterozygous mutation Sies C et al. NZ Med J 2005;118(1210):1324-30. Target Doses to Attain Therapeutic 6-TGN Levels Is 1 and 3 mg/kg/d in Intermediate and Normal Metabolizers Lower dose needed to get therapeutic for intermediate TPMT Even with dose adjustment, 6-TGN levels are lower when TPMT activity is higher Gardiner SJ et al, Clin Gastroenterol Hepatol 2008;6(6):654 660 October 2012 6
Target 6-TGN Level to Optimize Efficacy: >235 se quency of Respons Freq 100% 80% 60% 40% 20% 0% n=44 0-173 78% P< 0.001 41% Odds Ratio 5.0 for treatment response when 6-TGN > 235 n=42 174-235 n=43 236-367367 6-TGN QUARTILES Dubinsky MC et al, Gastroenterology 2000;118(4):705-13 n=44 368-1203 Meta-Analysis: Association Between 6-TGN Levels and Clinical Remission Author & Year Patients (Remission) 6TGN Threshold Fraction Above Fraction Below Odds Ratio 95% Confidence Threshold Threshold Interval Remission Remission Dubinsky 2000 92 (30) 235.78.40 5.07 2.62-9.83 Gupta 2001 101 (47) 235.56.43 1.65 0.73-3.75 Belaiche 2001 28 (19) 230.75.65 1.62 0.26-10.2 Cuffari 2001 82 (47) 250.86.35 11.63 3.78-35.7 Goldenberg 2004 74 (15) 235.24.18 1.47 0.47-6.42 Achkar 2004 60 (24) 235.51.22 3.80 1.17-12.4 Pooled Estimate 0.62 95% CI 0.43-0.80 0.36 95% CI 0.25-0.48 3.27 1.71-6.27 Osterman MT et al. Gastroenterology 2006:130(4);1047-1053 October 2012 7
Suboptimal 6-TGN Production Correlates With 6- MP Resistance Median change in 6-TGN Median change in 6-MMP * p=0.0003 p=0.0057 600 400 200 0-200 40000 30000 20000 10000 0 Non-Responders Responders Non-Responders Responders N=37 N=14 N=37 N=14 Dubinsky MC et al, Gastroenterology 2002;122(4):904-15. 6-MMP and Hepatotoxicity 6000 p < 0.05 5463 Median 6-MMP (pmol/8x10 8 RBC) 4000 2000 2213 0 n=157 n=16 Absent Present HEPATOTOXICITY Dubinsky MC et al, Gastroenterology 2002;122(4):904-15. October 2012 8
Allopurinol Therapy for Preferential 6-MMP Metabolism Pre-allopurinol Post-allopurinol 450 12000 400 350 10000 300 8000 250 200 6000 150 4000 100 50 2000 0 0 6-TG 6-MMP Allopurinol 100 mg added; 6-MP/AZA dose reduced to 25% to 50% of baseline Sparrow MP et al. Aliment Pharmacol Ther. 2005;22:441. Allopurinol Plus Thiopurine Might prevent non-hepatic adverse events as well (nausea, myalgia, fatigue): 88% success in one small study Needs to be done with extreme vigilance 100 mg allopurinol Dose reduce to 25% of original dose Weekly CBC for 4 weeks then monthly Periodic metabolites Ansari A et al, Aliment Pharmacol Ther 2010;31:640-7. Gearry RB et al, J Gastroenterol Hepatol 2010;25:649-56. October 2012 9
6-MP Metabolite Profiles 6-TGN 450 235 6-MMP 5700 Dose Too Low; Noncompliant Therapeutic Range Toxicity Preferential 6MMP Selective Monitoring Levels of Thiopurines is Useful Because. Standard dosing only 30% effective Safely dose escalate to maximize efficacy Identify non compliance Minimize toxicity Identify preferential 6-MMP metabolism Explain non response se Improve patient outcomes October 2012 10
Stopping Infliximab in Patients in Remission for 1 year on Combination Therapy Lemann M et al. Gastroenterology 2006;130(4):1054-1061. Multivariate Analysis of Factors Predicting Time to Relapse Lemann M et al. Gastroenterology 2006;130(4):1054-1061. October 2012 11
Infliximab Cessation GETAID study of 115 pts who after 1 yr had infliximab stopped and AZA continued 1 yr relapse rate was 44% Higher risk for relapse male, WBC > 6, Hgb < 14, CRP > 5, calprotectin > 300 Patients with < 2 risk factors only had 15% chance of relapse 88% of those re-treated achieved remission, 98% had response A gender based profile suggested Louis E Gastroenterol 2012; 142:63-70. Measuring Infliximab/ATI Newest assay measures both infliximab and Newest assay measures both infliximab and also antibody levels regardless of IFX level Measures any ATI Patient WILL pay for some of the test so tell patient first October 2012 12
Primary Indication for Infliximab/HACA Testing (n=155) Indication, n (%) Loss of response 76 (49) Partial response on initiation 34 (22) Autoimmune/delayed hypersensitivity reaction 16 (10) Primary non response 8 (5) Reintroduction after drug holiday 7 (5) Endoscopic/CTE recurrence 6 (4) Acute infusion reaction 5 (3) Unclear reason 3 (2) Afif W et al. Am J Gastroenterol 2010; 105:1133-9 Treatment algorithm in patients with clinical symptoms Positive HACA change to another anti-tnf agent increase IFX dose if no response, change to Rx with different mechanism of action (non anti-tnf agent) Afif W et al. Am J Gastroenterol 2010; 105:1133-9 October 2012 13
Treatment algorithm in patients with clinical symptoms Sub-therapeutic IFX concentration increase infliximab dose or frequency change to different anti- TNF agent If no response, change to different anti-tnf agent if no response, change to Rx with different mechanism of action (non anti-tnf agent) Afif W et al. Am J Gastroenterol 2010; 105:1133-9 Treatment algorithm in patients with clinical symptoms Therapeutic IFX concentration endoscopy/cte with active disease endoscopy/cte with inactive disease change to Rx with different mechanism of action (non anti-tnf agent) investigate for alternate etiology of symptoms Afif W et al. Am J Gastroenterol 2010; 105:1133-9 October 2012 14
Mucosal Healing in UC Endoscopic evaluation during ACT-1,2 Those with lower week 8 scores: Less likely to go to colectomy at 1 year Had better symptom scores Had better steroid use outcomes Degree of healing correlated with improved clinical outcomes Columbel JF. Gastroenterol 2011; 141(4):1194-201. Summary Routine TPMT testing prior to initiation of AZA/6-MP will reduce early leukopenia Thiopurine metabolite assay may help in non-responders or to monitor adherence For shunters consider allopurinol Requires dose reduction and close monitoring Incorporation of measurement of HACA and infliximab concentrations: Clinically useful Potentially avoid inappropriate management Optimize patient treatment algorithms When something does not make sense, go back to Square 1 October 2012 15
Adverse Events Do Not Outweigh Benefits of Combo Therapy in CD Decision model of 1 year use Only way that combination therapy more dangerous than beneficial is if 20% of population developed serious infection or 3.9% got lymphoma These thresholds h are 5-fold and d65-fold higher than reality Siegel C. Clin Gastro Hepatol 2012;10:46-51. Herbal Supplements Agent Action Aloe Reduces action of CS Cascara Reduces action of CS Chamomille, ginger, papaya Bleeding from coumarin component Rhubarb Reduces action of CS Licorice Prolongs CS half-life* Marshmallow Delays absorption *Inhibits 11-β hydroxysteroid dehydrogenase Hass DJ. Pharmacoepidemiology and Drug Safety 2006. October 2012 16
It s Not IBD Non-adherence Overlapping diagnosis: IBS Gender-specific conditions NSAID use Concurrent infections i Neoplasm No-no behaviors Alternate Diagnosis Ischemia Radiation Sprue Bechet s Yersinia SRUS Diverticulitis/SCAD October 2012 17