“Best Best of DDW DDW” Inflammatory Bowel B Disease Post-DD DW 2010 Laguna Niguel, N CA Southern Califoornia Society of Gastroen nterology “A taste off N’awlins” Top pics • Etiology of IBD • 5ASA and colorectal cancer c • Optimizing use of anti--TNF drugs – Crohn Crohn’s s disease – Ulcerative colitis – Special p Considerationss – Elderly, y, pregnancy p g y • New drugs / Pipeline • Predicting outcomes Etiologic Theories T in Inflammatory Bowel B Disease Genetic Predisposition IBD Mucosal Immune System (Innate/Adaptive Immune Dysfunction) Environmental gers Trigg Courtesy of S. Targan Etiologic Theories T in Inflammatory Bowel B Disease Intestinal infection “Hygiene yg hypothesis” yp IBD “Refrigerator Theory” Smoking Environmental gers Trigg “Stress” NSAIDS “Doc, is there anything a I was exposed to o as a child that gave me IBD?” Are there any modiffiable environmental risk factors f s ffor IBD? Do Antibiotic cs in Infancy Increase the Risk k of Pediatric IBD? • Population-based case e-control study in Manitoba • Antibiotic exposure in 1st year of life ’96 – ‘06 – 24 Cases: IBD (up to age a 11); 79% CD – 240 Controls: Matched d to age, sex, region • Average g # abx rx = 2.6 6 ((cases)) vs 0.9 ((ctrl)) – Most common reason: Otitis media – OR 5.8 (1.7 – 19.9) Shaw et al. DDW 2010. Abstract 95 Does Eatting Meat Increase the Risk of IBD? • Propective cohort of 67,581 French women – Self-administered diet surveyss every 2 years for avg. 10.4 yr – Validated V lid t d IBD di diagnoses OR 95% CI P value Total Protein Intake 3.31 1.41 – 7.77 0.007 Animal Protein Intake 3.03 1.45 – 6.34 0.005 •Association seen with meat, fish but not eggs, dairy •Associations Associations with both CD and U UC but ‘dose UC, dose-effect effect’ only seen in UC Jantchou et al. DDW 2010. Abstract # 98 Current Therap pies and Goals • Induce remission quickly • Maintain M i t i remission i i • Improved quality of life • Modify M dif llong tterm outcomes – Minimize hospitalization p and surgery – Minimize steroid exposure – Decrease disability • • • • • • Aminosalicyclates Corticosteroids Immunomodulators g Biologics Antibiotics Supportive agents 37 ym with UC U pancolitis doing well on 6MP Should he be on 5-ASA for chemoprevention off colorectal cancer? 5ASA Does NO OT Prevent CRC • Manitoba IBD database – 8939 subjects • Study I – Assess CRC rissk in users vs. non-users • Study II – Assess 5ASA use u in all 87 CRC cases – No difference in 5ASA use e in cases vs controls 5ASA use HR for CRC 95% CI P-value 1 yr 1.5 0.89 – 2.53 0.13 5 yr 2.7 1.19 – 6.18 0.02 Bernstein et al DDW 2010. #254 5ASA DOES Prevent CRC • CESAME cohort – 19,486 su ubjects j enrolled 2004-7 – 74 cases before and 79 cases after enrollment – 5ASA and IM use ‘the year of the t cancer’ assessed – IM do not prevent CRC: 0.71 (0 0.39 – 1.27) p=0.25 Group (number of cancers) All patients (n=153) UC (n=95) Crohn's disease ((n=58)) Pts at high risk* (n=94) Pts not at high risk (n=59) 5-ASA 5 0.55 [0.34-0.89] [ 0.52 [0.29-0.95] [ 0.62 [[0.27-1.40]] 0.46 [0.24-0.85] [ 0.75 [0.34-1.66] [ p-value p=0.01 p=0.03 p=0.25 p p=0.01 p=0.48 *high risk = disease >10 yrs, colon >50% involved Carrat et al. DDW 2010#255 18 yf, f hi history t off perianal p i l CD, CD doing d i well on infliximab,, starting g college g in the fall. “Doc Doc, can I switch to t a self-injectible? self injectible?” If a patient ti t is i in i remission, i i iis it ok k tto switch biolog gic therapy? Switch to Adalimumab in i CD Pts Controlled by Maintenance IFX: Prospectiv p ve Randomized Switch Study y Group A: ADA 50% 80 mg m SC → 40 mg SC EOW L LOR Ö Interval decrease (EW) N=36 INTOLERANCE or COMPLETE LOR IFX maintenance ≥ 6 months Symptom control CDAI <200 50% Group B: IFX L LOR Ö Interval decrease/ Dose increase (10 mg/kg) 5 mg/kg /k q6-8 6 8 wks k N=37 54 weeks V Assche et al, DDW 2010, Oral # 645. Van Switch to Adalimumab in i CD Pts Controlled by ve Randomized Switch Study Maintenance IFX: Prospectiv udy terminated early) Results Overview (Stu Group B IFX Group A ADA p=0.006 p=0.003 14% 28% 2% 84% 53% 19% stable t bl dose escallation early termination Van Assche et al, DDW 2010, Oral # 645 Switch to Adalimumab in CD Pts Controlled by Maintenance IFX: Prospectiv ve Randomized Switch Study • Majority preferred ADA A for maintenance, but significant proportion returned r to IFX due to intolerance to ADA • Electively switching ptts to a 2nd anti-TNF not recommended Van Assche et al, DDW 2010, Oral # 645. 24 yff on adalimu d li mab b 40 40mg every other week, sh howing signs of clinical atttenuation. How can we optimize adalimumab dosing? Recapturing respons se to ADA with microreinduction in patients p with CD • Retrospective, single center, n=20 n • CD p patients on ADA underwen nt micro-reinduction (mRI) ( ) • 80 mg dose EW for 2 weeks for loss of response • 12/20 ((60%)) p patients subjectiv j velyy improved p at week 12 – mRI may allow recapture off response to ADA treatment without p permanent dose esccalation Cassani et al. DDW 2010; Abstract W1315 Infliximab for Ulcerative U Colitis CLINICAL REMISSION R AT WE EEK 8 Rutgeerts et al. NEJM 2005 Infliximab as a res scue therapy for IV steroid reffactory UC IFX is approved for mod to severe UC, but b limited data on its use as rescue therapy for steroid refactory hospitalized d patients Colectomy Ra ate Colectomy free survival 1N=132, 72 males Mean age 39 3 pts t lost l t to t f/u f/ Wk 8: 21/132 (16%) Wk 52: 28/129 9 (22%) Wk52: 101/129 (78%) 13% IFX monotherapy 50% AZA monotherapy th 32% IFX+ AZA N=20, 10 males Mean age 30 2 pts lost to f/u 1 yr: 5/18 (28% %) 3/5 had conco omittant C. difficile 2 yr:13/18 (72%) 50% required IFX dose optimization 25% IFX + IMM 2 Conclusions: IFX is effective rescue therapy fo or colectomy free survival, pair with immunmodulators 1. Monterubbianesi et al DDW 2010 W1257 2. Venu et al DDW 2010 W1296 Efficacy and safety of In nfliximab rescue therapy after cyclosporin failure e in steroid refactory UC • • • 51 IV steroid refactory UC pts treate ed with IFX after CSA failure (78% IV CSA, 22% oral CSA) Median time from last CSA to first IFX 12 days Results: 15 (29.4%) went for colectomy over median 5 weeks Remission R Response Colectomy IFX #1 #1, nn=51 6 (12%) 39 (76%)) 6 (12%) IFX #3 #3, n=39 23(59%) 12(31%) 4 (10%) •Adverse event rate 25%: 6 infections, 1 leukopenia, 1 bowel perforation, 1 fever, 1 death (40 yr m, surgery 10d affter 1st IFX, died of pneumonia) •Conclusion: Rate of adverse events and a mortality, mortality decision of sequential CSA-IFX should be individualized Chaparro et al. DDW 2010 W1274 Does adalimuma ab ‘work’ ab work for UC? Adalimumab for Induction n of Clinical Remission in M d Moderately t l to t Severely S l Active A ti Ul Ulcerative ti Colitis C liti Primary Endpoint: Clinical Remission at a Week 8 Proportio on of Patients (%) 20 * 18 5 18.5 15 † 10 9.2 10 5 24/130 12/130 13/130 Placebo A ADA 80/40 0 ADA 160/80 *pp=0.031 0.031 vs. placebo † p=0.833 vs. placebo Reinisch et al, DDW 2010, Oral # 847t Ulcerative e Colitis CLINICAL REMISSION AT WEEK 8 CLINICAL REMISSION AT WEEK 8 Reinisch et al, DDW 2010, # 847t Rutgeerts et al. NEJM Feb 2005 Secondary Endpoints Placebo (N=130) ADA 80/40 (N=130) ADA 160/80 (N=130) Clinical response 44.6% 51.5% 54.6% Mucosal healing 41 5% 41.5% 37 7% 37.7% 46 9% 46.9% Rectal bleeding subscore ≤ 1 66.9% 70.0% 77.7%* PGA subscore ≤ 1 46.9% 53.8% 60.0%† Stool frequency subscore ≤ 1 37.7% 36.2% 49.2%‡ *p=0.052, †p=0.035, ‡p=0.061 vs. placebo. Reinisch et al, DDW 2010, Oral # 847t Are there imporrtant differences among the 3 anti-TNFs? Placentall transfer.. % Ex-Vivo placental transfe er of Anti-D IgG antibody certolizum mab pegol g Anti-D IgG G Certolizumab p pegol g by y Bioassay y 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 1 2 3 4 P Placentas 5 6 Certolizumab pegol was detected in the e fetal circuit of 2 placentas placentas, certolizumab pegol in these samples (0.15% and 0.009%) was lower than the amount of anti-D IgG (0.60% and 0.39%, respectively) Porter et al. DDW 2010. Abstract W1208 What drugs s are being studied for f IBD? “N “Negativ tive Trials” Ti l ” • Abatacept (anti-CTLA4, Orencia O ®) for CD – Phase III RCT study termin nated early due to lack of efficacy in induction phase e (12 weeks) • VSL #3 – Placebo-Controlled trial forr maintenance of remission in 30 patients on stable 5ASA A or IM – At 1 year, 9 flares total (8 in VSL#3, 1 in placebo) • Rituximab (anti (anti-CD20, CD20, Rituxan ®) for UC (phase II) – Primary endpoint remission at 4 weeks – 3/16 rituximab vs 1/8 place p ebo ((NS)) – Role for higher dose? Hanauer a aue et a al DDW 2010 0 0 #6 #649 9 Willert et al DDW 2010 T1235 Leiper et al DDW 2010 648 Low-Dose Naltrexone • Endogenous opioids “play a role” in “healing of tissues” • Randomized, DB, placebo-c p controlled trial of LDN 4.5mg/d in adults with CDAI >220, single crossover a baseline, Weeks 12 and 24 • Colonoscopies performed at • Primary outcomes: CDAI, endoscopic e and histologic inflammatory scores • 40 patients enrolled Low Dose Naltrexone Low-Dose • CDAI scores decreased significantly sg y from baseline (p<0.001) in those treated d with LDN – 82% of LDN-treated patien nts had at least a 70-point drop i th in the CDAI score – Unclear what placebo resp ponse was (not in abstract) – Endoscopy and histology sscores improved in LDN LDN-treated treated patients (p=0.002) • Unconventional presenta p tion of data – CDAI scores at week 0 vs week 12 was primary endpoint – NO DIRECT COMPARISO ON TO PLACEBO group Smith J et al. DDW 2010 Abstract # 646 “The The Piipeline ipeline” CCX282-B (T Traficet-EN ®) • Oral CCR9 antagonist for mod derate-to-severe Crohn’s • Methods: Randomized, double e-blind, placebo-controlled trial • Maintenance 36 weeks after 12-week induction and 4-week open-label – Endpoints: CDAI response and Remission at 36 weeks • Results: 241 pts randomized Remission (%) 100 Placebo (n=146 6) CCX282-B (n=95) 80 60 50 47 44 47 40 4 42 50 49 38 47 31 20 P=0.01 0 Wk 4 Wk 12 W 20 Wk Wk 28 Wk 36 Keshav et al DDW 2010 #647 HMPL00 04 in UC Andrographiis Paniculata • Indigenous medicinal plant from Southeast Asia • Anti-inflammatory A ti i fl t properties, ti use ed d for thousands of years; mixture of o active compounds p • Mouse data (prelim) with reduce ed intestinal inflammation, IL6, TNF Fa • Double D bl bli blind d phase h II RCT ffor mildmild moderate UC, 223 patients • Remission and mucosal healing at week 8 (dose-dependent respon nse) Sandborn et al DDW 2010 #847 Should we be thinking t g about biologics differently in special pop pulations? What are the risks of biologic b therapy in the eldeerly? What are the risks of biolo ogic therapy on pregnancy and the first year of life fe in an exposed infant? Elderly and Immunosuppressive medications • Elderly patients, 5 time es more likely to have infectious complication p ns if on immunomodulators1 • Older age not associated with adverse events from biologic therapy iin IBD2 1.Lin et al. DDW 2010 W1201 2.Bushan A DDW 2010 #413 Impact of IBD medicatio on exposure on newborn develo opment PIANO registry interim analysis of 521 patients 353 completed pregnancy, 339 live births Newborns reaching development milestones Drug g exposure p (Denverr Childhood Developmental Score) Month 4 Month 9 Month 12 Control n=136 89 (92.8%) 69 (90.6%) 56 (86.1%) IS (AZA/6-MP) n=79 53 (93.2%) 41 (82.3%)** 33 (84.2%) Anti-TNF n=124 88 (94.8%) 60 (91.3%) 39 (89.6%) * 39 women took both an IS and an anti-TNF agent ** p=0.04 – IS may result in a statistically lower number of newbo orns reaching developmental milestones at Month 9 Mahadevan et al. DDW 2010; Abstract 764 Patients with Corticosteroid d-free Clinical Remission (Panel A) and Mucosal Healing (Panel B) at Week 26 SON NIC • 508 adults with CD • Naïve to IM and biologics • Randomized to – AZA 100 – IFX 5mg/kg – AZA + IFX • Followed 1 yr with CDAI, colonoscopy, l d drug llevels l Colombel et al. NEJM Feb 2010 Who should be b treated a la SON NIC? Can we predict wh ho is most likely to benefit from this tre eatment approach? Probabillity of no on-progre essive C CD Antibody Sum Predict Earlier Surgery in Cro ohn’s Disease 1.00 N= 189 N= 243 0.75 N 47 N= P<0.0001 0.50 N= 174 ab_sum=0 _ ab_sum=1 ab_sum=2 ab_sum=3 0.25 0.00 0 25 50 75 100 125 150 175 Time to su urgery (months) Dubinsky, M., et al Clin Gastroenterol Hepatol. 2008 Jul 9 . Predicting Prognosis s of Crohn’s Disease ( k Wh (aka. Who should h ld gett ‘Top ‘T Down’ D ’ therapy?) th ?) • 619 CD patients asses ssed for clinical and NOD2 mutations predictors,, serologies p g QSS Very Low (6-11) (6 11) Low (12-14) Medium ((15-17)) High (18-20) Very High (21-24) n 88(14%) 130 (21%) 168 ((27%) 148 (24%) 85 (14%) Complications 23% 46% 55% 79% 79% Surgery 10% 22% 35% 49% 64% Lichtenstein et al. DDW 2010 #207 Shifting Treatm ment Paradigms Better Drug Levels Lower Antibody Levels Muco osal Healling Early Treatment Conco omitant Anti--TNF And d IM Anti-TNFs and Mucosal M Healing • MUSIC – Certolizumab le eads to mucosal healing – 89 pts, CDEIS 14.5 Æ 8.3 (wk 10) and 9.6 (wk 54) • EXTEND – Adalimumab leads to mucosal healing – Those with early healing (S SES < 5 at week 12) had significantly better CDAI sccores and remission at week 52 • Higher infliximab trough le evels are associated with mucosal healing in Crohn n’s n s disease – Serum samples in 210 pattients treated with IFX Van Moerkercke W et al DDW 2010 #405 Colombel et al. DDW 2010 S1045, T1239 Rutgeerts et al DDW 2010 644 Infliximab an nd ATI levels • Many patients ‘attenuate’ to infliximab over time – Antibodies to IFX, increase ed drug clearance • Drug trough levels are hig gher in those who maintain response (and ATI are low wer) • Assays available to meassure drug and ATI levels – Cutoff levels not determine ed • Methods: Retrospectivelyy classified CD/IFX – Maintenance Responders, Secondary NR, Primary NR o cut-off levels – ROC curves to determine optimal Steenholdt et al. DDW 2010 #1270 “My My patient los st effect to IFX” IFX How to interrpret ‘levels’ Hig gh anti-Drug Antibodies A (>10 U U/mL) Low anti-Drug Antibodies (<10 U/mL) Low Infliximab Level ((<0.5 ug/mL) g ) High Infliximab Level (>0.5 ug/mL) Steenholdt et al. DDW 2010 #1270 “My My patient los st effect to IFX” IFX Treatment Algorithm Hig gh anti-Drug Antibodies A (>10 U U/mL) Low Infliximab Level ((<0.5 ug/mL) g ) Low anti-Drug Antibodies (<10 U/mL) Problem: Ellimination of IFX due to antibodies Solution: Change to another antiTNF g Infliximab Level High (>0.5 ug/mL) Steenholdt et al. DDW 2010 #1270 “My My patient los st effect to IFX” IFX Treatment Algorithm Low Infliximab Level ((<0.5 ug/mL) g ) Hig gh anti-Drug Antibodies A (>10 U U/mL) Low anti-Drug Antibodies (<10 U/mL) Problem: Ellimination of IFX due to antibodies Solution: Change to another antiTNF Problem: Pharmacokinetic Solution: Increase IFX dose or frequency g Infliximab Level High (>0.5 ug/mL) Steenholdt et al. DDW 2010 #1270 “My My patient los st effect to IFX” IFX Treatment Algorithm Low Infliximab Level ((<0.5 ug/mL) g ) g Infliximab Level High (>0.5 ug/mL) Hig gh anti-Drug Antibodies A (>10 U U/mL) Low anti-Drug Antibodies (<10 U/mL) Problem: Ellimination of IFX due to antibodies Solution: Change to another antiTNF Problem: Pharmacokinetic Solution: Increase IFX dose or frequency Problem: Pharmacodynamic Solution: Review history, y, change g class Steenholdt et al. DDW 2010 #1270 “My My patient los st effect to IFX” IFX Treatment Algorithm Hig gh anti-Drug Antibodies A (>10 U U/mL) Low anti-Drug Antibodies (<10 U/mL) Low Infliximab Level ((<0.5 ug/mL) g ) Problem: Ellimination of IFX due to antibodies Solution: Change to another antiTNF Problem: Pharmacokinetic Solution: Increase IFX dose or frequency g Infliximab Level High (>0.5 ug/mL) Problem: ??? Solution: Repeat R test Problem: Pharmacodynamic Solution: Review y, change g class history, Steenholdt et al. DDW 2010 #1270 Summary “Themes” Themes DDW 2010 • Ongoing controversies s – IFX for hospitalized UC C – Who to treat with ‘Top Down’ approach – Should one continue 5ASA purely for chemoprevention • Anti Anti-TNFs TNFs are not omn ni equivalent ni-equivalent – UC, pregnancy Summary “Themes” Themes DDW 2010 • Optimize what we hav ve, because we don’t have a lot of drugs g – Don’t switch if doing we ell – Consider ‘micro-reindu micro reindu uction’ for adalimumab uction attenuators – Drug g levels can help p decision making g for infliximab attenuation