Agenda. Predictive markers in IBD. Management of ulcerative colitis. Management of Crohn s disease

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2 Agenda Predictive markers in IBD Management of ulcerative colitis Management of Crohn s disease 2

3 Patients With UC (%) Distribution of UC Disease Severity at Presentation 1 Fulminant disease (9%) Moderate to higher activity (71%) N=1,161 2 Low activity (2%) Disease Activity Langholz EP et al. Scand J Gastroenterol. 1991;26:

4 Patients With UC (%) Course of UC 1 8 Disease Course One Year After Diagnosis Moderate-high activity (2%) 4 3 Colectomy Rate (%) 6 Low activity (3%) No symptoms (5%) 1 Disease activity Years Hendriksen C et al, Gut. 1985;26:

5 Predictors of Poor Response or Colectomy 1-5 Serum albumin ESR >3 mm/h Bandemia Prolonged flare Active infection Hospitalization setting 5 Severe endoscopic lesions 4 Stool frequency 1 Percentage of bloody stools 1 Body temperature >37.5 C 1,4 Heart rate >9 bpm 4 Increased CRP 1,2,4 Toxic megacolon Low hemoglobin <1.5 g/dl Disease duration 3 BPM=beats per minute; CRP=c-reactive protein; ESR=erythrocyte sedimentation rate. 1. Lindgren SC et al. Eur J Gastroenterol Hepatol. 1998;1: ; 2. Gonzalez-Lama Y et al. Hepatogastroenterology. 28;55: ; 3. Suzuki Y et al. Dig Dis Sci. 26;51: ; 4. Cacheux W et al. Am J Gastroenterol 28;13: Ananthakrishnan AN et al. Am J Gastroenterol. 28;13:

6 Impact of Mucosal Healing on Disease Course in UC 6

7 Mucosal Healing as a Surrogate for Longer-Term Outcomes Associated with: Better quality of life Fewer hospitalizations Fewer surgeries Longer time to clinical relapse Reduction in dysplasia/cancer Sands, B. ACG-FDA Workshop 212 7

8 Mucosal Healing: Added Value Beyond Clinical Remission? Support for biologic plausibility of clinical remission Increased specificity of clinical remission Surrogate marker for longer-term outcomes Sands, B. ACG-FDA Workshop 212 8

9 Proportion of UC patients not colectomised Impact of Mucosal Damage on Subsequent Resection in a Population Series: UC 1,,98,96 Patients without endoscopic activity at 1- year visit,94,92 Patients with endoscopic activity at 1-year visit, Time in years after 1 year visit Frøslie KF, et al. Gastroenterology. 27;133: Patients with compromised mucosa 1 year after diagnosis showed a trend toward more surgeries. 9

10 Mucosal Healing and Time to Colectomy in Infliximab-treated Patients P< Time to coloectomy infliximab use (weeks) = NORMAL endoscopy subscore = endoscopy subscore = 1 endoscopy subscore = 2 endoscopy subscore = 3 1 = MILD 2 = MODERATE 3 = SEVERE Colombel JF et al. Gastroenterology. 211;141:

11 Patients (%) The Majority of IBD Patients in Clinical Remission Have Mucosal Inflammation 5 Frequency of Mucosal Healing in Patients Without Clinical Symptoms n=47 n=51 n=47 n=51 n=51 No endoscopic inflammation + Endoscopic & histologic inflammation n=51 + Histologic inflammation 2 n=2 + Endoscopic inflammation Baars JE et al. Inflamm Bowel Dis. 212;18(9):

12 Poor Correlation Between Mucosal Healing and Clinical Remission With Infliximab in ACT 1 Trial Week 8 Week 3 Week 54 Patients (%) Patients (%) Patients (%) * 62 * 39 Mucosal healing Clinical remission * 5 * 34 Mucosal healing Clinical remission * 46 * 35 Mucosal healing Clinical remission Placebo (n=121) Infliximab 5mg (n=121) Placebo (n=121) Infliximab 5mg (n=121) Placebo (n=121) Infliximab 5mg (n=121) *P.1 vs placebo based on a two-sided Cochran-Mantel-Haenszel X 2 test Mucosal healing = Mayo score or 1 Rutgeerts et al. N Engl J Med. 25;353(23):

13 Interpreting Discordance of Clinical Remission and Mucosal Healing Mucosal Healing+ Mucosal Healing- Clinical Remission + True remission Clinical remission driven by placebo response? Clinical remission driven by pharmacologic effects other than direct effect on inflammation? Clinical Remission - Other conditions driving symptoms (e.g. IBS) Irreversible disease complications driving symptoms (e.g. fibrosis, lead pipe rectosigmoid) True lack of response Modified from Sands, B. ACG-FDA 212 Workshop 13

14 Histologic Inflammation Predicts Relapse in UC Patients with relapse (%) 1 Acute inflammatory cell infiltrate (N=27) Patients with relapse (%) 1 Crypt abscesses (N=27) 52% P=.2 78% P<.5 25% 27% Infiltrate No infiltrate Patients with Mucin depletion (N=27) relapse (%) 1 P<.2 56% Patients with relapse (%) 1 Presence 75% Absence Breaches in surface epithelium (N=27) P=.1 26% 31% Depletion Riley SA et al. Gut. 1991;32: Presence Presence Absence 14

15 Surrogates for Mucosal Healing in UC (Endoscopy is Not an Ideal Surrogate Measure) Candidates include: CRP, fecal leukocyte markers CRP: Clinically useful, nonparametric distribution, large variances, nonproduction Calprotectin, fecal lactoferrin: Differential expression by disease and anatomical location, role in predicting relapse Modified from Feagan, B. ACG-FDA Workshop,

16 % of Patients Use of Fecal Calprotectin as Marker of Disease Activity in Patients Taking Maintenance Infliximab for UC # of Patients N=113 UC patients on infliximab 5 mg/kg in stable remission with 5 mg/kg infliximab q8w. Fecal calprotectin (FC) measured monthly for 1 year Deep remission (DR) = normal endoscopy at baseline and week 52 + Mayo score < 3 Active disease = clinical Mayo score or endoscopic score 2 at week year outcome /113 3/113 28/113 Remission DR Discontinued FC levels highly correlate with disease activity in pts on IFX maintenance therapy for UC. DR is associated with very low levels of FC. A flare is associated with high levels (median >3 mg/kg). Two consecutive levels of >3 mg/kg predict a flare. Median FC < 5 mg/kg at all measured time points Reason for D/C 5 16 Flare Safety Withdrew consent Median FC 477 mg/kg. Increase in FC observed already 3 months prior. Two consecutive FC measurements >3 mg/kg predicted flare De Vos M et al. Presented at ECCO 212; February 16-18, 212; Barcelona, Spain. Abstract OP7. 16

17 Mucosal Healing in UC Mucosal healing (by whatever criteria) is associated with improved outcomes (histologic>endoscopic>clinical) No validated definitions of: Endoscopic/histologic healing Significant intra/inter-observer variations No validated surrogates Practicality of achieving mucosal healing (by whatever criteria) in clinical trials/clinical practice Is almost as good as complete? 17

18 Sequential Therapies for UC Disease Severity at Presentation Severe Anti-TNF Cyclosporine Colectomy Anti-TNF Thiopurine Moderate Corticosteroid Aminosalicylate Thiopurine Mild Aminosalicylate Aminosalicylate Induction Maintenance Therapy is stepped up according to severity at presentation or failure at prior step 18

19 Summary of UC Therapies Mesalamine (oral ± topical) induction and maintenance for mild-moderate disease Corticosteroid induction for moderate-severe disease Thiopurines maintain steroid-induced remission Anti-TNF agents for steroid-refractory induction or steroid-dependent maintenance (± thiopurine) 19

20 Clinical Predictors for Disabling Crohn s Disease Age of onset [below 4 years of age] (P=.4) Small bowel disease location (P=.2) Perianal lesions at diagnosis (P=.1) Need for steroids at first flare (P=.1) Current smoker (P=.9) P values reflect non-disabling vs. disabling CD Beaugerie L et al. Gastroenterology. 26;13:

21 Patients (%) Points D Haens Study: Mucosal Healing Improved With Top-down Strategy Mucosal Healing * 88 # 1 8 Early combined immunosuppression (n=24) Conventional management (n=2) # 2.15 Complete Ulcer Healing 1 Reduction 2 Endoscopic healing was scored in 5 ileal and colonic segments as follows: =no ulcers, 1= aphthoid ulcers, 2=larger ulcers, 3= ulcerated stenosis. * P=.28; # P<.1 1. D Haens G et al. Lancet. 28;371: D Haens GR et al. Gastroenterology. 26;13:A-11. Abstract 764. Reduction in Endoscopic Score 1 21

22 Serum Markers for IBD Marker Prevalence ASCA (or other anti-glycans) 35% 76% of CD patients 1,2 Anti-CBir1 5% 55% of CD patients 3 Anti-OmpC 55% of CD patients 4 Anti-I2 54% of CD patients 5 IBD-specific (DNase) panca 1% 25% of CD patients 4% 6% of UC patients panca 3% 83% of UC patients 1 1. Sandborn WJ. Rev Gastroenterol Disord. 24;4: ; 2. Dotan I et al. Gastroenterology, 26:131: ; 3. Targan SR et al. Gastroenterology. 25;128:22-228; 4. Landers CJ et al. Gastroenterology. 22;123: ; 5. Sutton CL et al. Gastroenterology. 2;119:23-31; 22

23 Risk of Disease Progression Increases With Increased Serum Immune Responses CLINICAL PHENOTYPE NUMBER OF ANTIBODIES TOWARD MICROBIAL ANTIGENS* P trend ODDS RATIO (3 vs ) 95% CI (3 vs ) Fibrostenosing (%) < Internal perforating (%) < Small bowel surgery (%) < *Percentage of patients with a specific disease phenotype; antigens include: I2, OmpC (outer membrane porin C), and ASCA (anti-saccharomyces cerevisiae). Results are irrespective of panca and NOD/CARD15 status. Mow S et al. Gastroenterology. 24;126:

24 Probability of non-progressive CD Prediction of Internal-Penetrating / Stricturing Disease: Quantitative Assessment With Antibody Sum Survival estimates according to antibody sum 1 ab_sum=1 ab_sum=.75 ab_sum=3 ab_sum= P< Time to IP/S Behavior (mo) Markers assessed included ASCA (anti-saccharomyces cerevisiae), OmpC (outer membrane protein complex), CBir1 (flagellin). CD = Crohn s disease; IP/S = internal-penetrating/stricturing Dubinsky M et al. Clin Gastroenterol Hepatol. 28;6:

25 Sensitivity (True positive) Receiver-Operator Curves for Individual Markers Marginal Discrimination: IBD vs. non-ibd Test AUC ANCA ELISA.685 ASCA-IgA.734 ASCA-IgG.723 CBir1.641 OmpC.7 No Discrimination Specificty (False positive) Plevy SE, et al. Presented at DDW; May 19, 212. San Diego, CA. Abstract

26 Sensitivity (True positive) 1. ROC Curve for Combined Serology Testing Test AUC IBD S7.843 ANCA ELISA.685 ASCA-IgA.734 ASCA-IgG.723 CBir1.641 OmpC.7 No Discrimination Specificty (False positive) Plevy SE, et al. Presented at DDW; May 19, 212. San Diego, CA. Abstract

27 In contrast to clinical remission in Crohn s disease, maintenance of endoscopic remission does influence longterm course 27

28 % of Patients in Remission Mucosal Healing Predicts Sustained Clinical Remission in Early CD Simple endoscopic score at year 2 Simple endoscopic score 1-9 at year Remission on Steroids Off Steroids and No Anti-TNF During Years During Years Baert FJ et al. Gastroenterology. 21;138:

29 Rate of Hospitalizations and Surgeries (%) Infliximab: Endoscopic Healing and Reduced Hospitalizations and/or Surgeries Hospitalization Surgery Patients with no healing (n=74) Patients with healing at 1 visit (1 or 54 weeks) (n=16) Patients with healing at both visits (1 and 54 weeks) (n=9) Rutgeerts P et al. Gastroenterology. July 22;123(1) Suppl:43. Abstract no. M

30 EXTEND: Patients Who Achieved Deep Remission * with Adalimumab at Week 12 and Hospitalization Rates All hospitalization (%) CD-related hospitalization (%) All-cause hospitalization through Week 52 CD-related hospitalization through Week /11 9/53 Deep remission * (Week 12) Non-deep remission * (Week 12) /11 5/53 Deep remission * (Week 12) Non-deep remission * (Week 12) * Deep remission defined as clinical remission (CDAI <15) and complete mucosal healing in EXTEND CDAI=Crohn s disease activity index Colombel JF et al. Gut. 21;59(Suppl 3):A8. 3

31 Impact of Biologic-induced Deep Remission 31

32 Discontinuation of Infliximab in Patients in Stable Remission on Combination Therapy (Azathioprine Maintained) ±4% 79±4% ±5% 56±5% 5±5% 5±5%.2 52 relapses in 115 patients Median (±SE) follow up 21 ± 1 mo 52 relapses in 115 patients Median (±SE) follow up 21 1 mo Months Since Inclusion # at risk : Louis E et al. Gastroenterology. 212;142:

33 Multivariate Analysis of Factors Predicting Time-to-Relapse: Factor HR (95%CI) P Male 3.7( ) <.1 No surgery 4. ( ).1 Steroid treat. (month -12 to -6) 3.5 ( ).3 Hemoglobin 14.5 (g/dl) 6. ( ) <.1 WBC > 6 (1 9 /L) 2.4 ( ).1 CRP hs 5 (mg/l) 3.2 ( ) <.1 CDEIS > 2.3 ( ).4 CDEIS=Crohn s disease endoscopic index of severity. Louis E et al. Gastroenterology. 212;142:

34 Predictive Model for Time-to-Relapse Kaplan Meier time-to-relapse curves according to multivariate models and scores generated through Cox model using multiple imputations method Deleterious factors: No previous surgery Steroids within 12-6 months before infliximab withdrawal Male gender Hemoglobin 14.5 g/dl, Leukocyte count >6x1 9 /L, hscrp 5 mg/l, Fecal calprotectin 3 µg/g, CDEIS>, infliximab trough 2 mg/l Louis E et al. Gastroenterology. 212;142: Proportion Without Relapse Months since infliximab withdrawal No. deleterious factors < >6 34

35 Concept Deep remission (clinical, biologic, endoscopic) is associated with improved outcomes However, maintenance therapy is still required Analogous to postoperative remission 35

36 Patients (%) Prevention of Endoscopic Recurrence in Postoperative Crohn s Disease: Infliximab 9 Infliximab (N = 11) Placebo (N = 13) Infliximab vs placebo P= /11 11/13 Recurrence Endoscopic Recurrence defined as endoscopic scores of i2, i3, or i4. Regueiro M et al. Gastroenterology. 29;136:

37 % of Patients in Remission Mucosal Healing Predicts Sustained (2-year) Clinical Remission in Early CD Simple endoscopic score at year 2 Simple endoscopic score 1-9 at year Remission on Steroids Off Steroids and No Anti-TNF During Years During Years Baert FJ et al. Gastroenterology. 21;138:

38 Cumulative Probability (%) Impact of Therapy Depends on Degree of Structural Damage and Velocity of Progression 1 9 High Potential Low Potential Penetrating Inflammatory Stricturing 12 Patients at risk: Months N = Cosnes J et al. Inflamm Bowel Dis. 22;8(4):

39 Remission (%) CHARM: Remission by Disease Duration With Adalimumab at Week 26 Placebo All adalimumab P=.8 46 P= P< <2 years n=23, n=39 <2-5 years n= 36, n=57 5 years n=111, n=233 Schreiber S et al. Journal of Crohn s and Colitis (212), doi: 1.116/j.crohns

40 Patients in Deep Remission* at Week 52 (%) EXTEND: Disease Duration and Deep Remission* Rates Placebo Adalimumab 4 mg eow /9 3/9 /15 2/11 /41 7/44 2 years >2 to 5 years Disease Duration >5 years *Deep remission defined as clinical remission (CDAI <15) and complete mucosal healing in EXTEND P<.1 for adalimumab vs placebo, adjusted for baseline disease duration (Cochran-Mantel-Haenszel test) All patients (n=135) received adalimumab 16/8 mg induction therapy, before randomization (n=129) to adalimumab 4mg eow or to placebo CDAI=Crohn s disease activity index; eow=every other week. Colombel J et al. Inflamm Bowel Dis. 211;17:S44. Abstract P

41 % in CDAI Response or Remission n=19 n=35 n=19 n=35 n=2 n=22 n=2 n=22 n=45 n=55 n=45 n=55 n=131 n=98 n=131 n=98 Response and Remission to Certolizumab Pegol in Crohn s Disease vs Disease Duration 1 9 9% % 68% 37% 75% 5% 55% 36% 62% 36% 47% 29% 57% 33% 44% 24% 1 Data from the PRECiSE 2 study <1 Year 1 to <2 years 2 to <5 years 5 years Response Placebo Response Remission Placebo Remission Schreiber S. et al. Am J Gastroenterol. 21;15:

42 Sequential Therapies for Crohn s Disease Disease Severity at Presentation Severe Anti-TNF Natalizumab Anti-TNF+/- Thiopurine/MTX Moderate Corticosteroid Thiopurine/MTX Mild Aminosalicylate Budesonide Aminosalicylate Budesonide/Thiopurine Induction Maintenance Step-up according to severity at presentation or failure at prior step 42

43 Disease activity Accelerated Step-Care Therapy with Early Azathioprine (e-aza) Versus Conventional Step- Care Therapy in CD: A Randomized Study Percent Aim: To compare accelerated stepcare strategy with early AZA (IMS) versus conventional step-care therapy in patients with early CD and predictors of disabling disease (age at diagnosis <4, steroid use at first flare, perianal disease) N=71 Accelerated Step-Care (e-aza) e-aza 142 patients N=71 Conventional Therapy Primary Endpoint Controls IMS + Anti-TNF IMS + Anti-TNF 4 2 IMS + Corticosteroids Corticosteroids Conventional Therapy IMS + Corticosteroids Accelerated Step-Care AZA=azathioprine; IMS=immunosuppressor; TNF=tumor necrosis factor Cosnes J, et al. Presented at DDW; May 22, 212. Abstract 943c. Total Early AZA use in patients at high risk for disabling disease has no significant impact on the subsequent 3-year CD course. Conventional therapy could allow physicians to vaccinate patients before immunomodulator therapy. 43

44 Evolving Goals of Therapy for IBD: Sustained Deep Remission Goal Response Clinical Parameters Improved symptoms Outcomes Improved QoL Remission No symptoms Normal labs Decreased hospitalisation Deep remission Normal endoscopy Mucosal healing Avoidance of surgery Minimal/no disability SUSTAINED QoL=quality of life Modified from Panaccione R. Presented at: European Crohn s and Colitis Organization (ECCO) Fifth Annual Congress. Prague, Czech Republic; February 21 44

45 Maintenance with Biologics can be Optimized by Pharmacology and Determination of Trough Levels 45

46 Percent of patients (%) Corticosteroid-Free Clinical Remission at Week 5 1 Patients with CRP.8 mg/dl and Lesions on Baseline Endoscopy* P=.2 8 P=.16 P= /75 27/65 32/64 AZA+ placebo IFX + placebo IFX + AZA * Patients who did not enter the study extension were treated as nonresponders AZA=azathioprine; IFX=infliximab Colombel JF et al. N Engl J Med. 21;362:

47 Proportion of Patients (%) Steroid-Free Clinical Remission at Week 26 by Antibody to Infliximab Status at Week /185 12/18 9/16 Inconclusive Negative Positive ATI=AZA=azathioprine; IFX=infliximab Colombel JF et al. N Engl J Med. 21;362:

48 Median serum IFX concentration* at Week 3 (mcg/ml) Median Serum Infliximab Levels at Week P< IFX + Placebo (n=97) IFX + AZA (n=19) * IFX + placebo- or IFX/AZA-treated patients who had serum samples collected prior to infusion at Week 3 (N=26) AZA=azathioprine; IFX=infliximab Colombel JF et al. N Engl J Med. 21;362:

49 Steroid-free Clinical Remission at Week 26 by Median Trough IFX Concentration at Week 3 (SONIC) Proportion of Patients (%) /32 13/23 43/59 36/49 31/43 >-1 >1-3 >3-6 >6 IFX + placebo or IFX/AZA-treated patients who had serum samples collected prior to infusion at Week 3 (N=26) IFX=infliximab Colombel JF et al. N Engl J Med. 21;362:

50 Infliximab Trough Levels and CRP During Infliximab-Immunomodulator Combination Treatment Objective To study the influence of immunomodulator withdrawal on infliximab trough levels and to identify predictors of disease flare and loss of response to infliximab after withdrawal of immunomodulators Patients (N=223) On infliximab maintenance therapy for CD, of whom 155 were cotreated with immunomodulators Treatments Immunomodulators discontinued in 117 patients when durable clinical remission was achieved after >6 months of cotreatment Drobne D et al. Gastroenterology. 211;14(5, Suppl 1):S-62. Abstract

51 No loss of response Loss of Response After Immunomodulator Withdrawal 1 Stop of Infliximab Due to Loss of Response after Immunomodulator Withdrawal 8 6 TL detectable & CRP <5 mg/l TL detectable & CRP >5 mg/l TL undetectable & CRP >5 mg/l Months TL=trough levels Drobne D et al. Gastroenterology. 211;14(5, Suppl 1):S-62. Abstract

52 Conclusions Undetectable infliximab trough levels and CRP >5 mg/l during combination therapy are associated with an increased loss of response to infliximab after immunomodulator withdrawal Drobne D et al. Gastroenterology. 211;14(5, Suppl 1):S-62. Abstract

53 Maintenance of Biologic Trough Levels High dose-induction followed by maintenance therapy Combination therapy to reduce immunogenicity 1 Avoid drug holidays 1 Monitor trough levels 1 to avoid Biologic relapse Development of immunogenicity Ordas I et al. Clin Gastroenterol Hepatol, (1):

54 Summary Personalized management for IBD depends on: Disease severity at presentation Clinical and biologic prognostic factors Achievement of clinical and biologic remission Maintenance of clinical and biologic remission Patient adherence Therapeutic monitoring 54