11/10/2014. New Treatments in IBD: When, Whom and How. Background. Background. Options. Disease Assessment. What is the evidence?

Transcription

1 New Treatments in IBD: When, Whom and How. Background Options Disease Assessment What is the evidence? Kofi Clarke MD, FACP,FRCP (Lond) Clinical Associate Professor, Chief, Gastroenterology, Hepatology and Nutrition Allegheny Health Network. Should we stop treatment? Background million people Huge Health care implications Genetics and Environment 59 SNPs for UC ; 71 for Crohns Younger Population Variations in incidence and prevalence Loftus EV; 2007 Dec;5(12): Nat Genet.2010 Dec;42(12): Nat Genet.2010 Apr;42(4): Prevalence of IBD: Whites > Blacks/Hispanics /Asians (all p < 0.05, except for UC in Asians) Differences in Crohn's disease between Whites and minorities and the difference in UC between Whites and Blacks remained significant in multivariate analysis No regional difference in the prevalence of Crohn's disease, but the prevalence of UC was higher in the Northeast than the South (p < 0.05). 1

2 Treatment Options Spectrum Indications Pre treatment and Monitoring Side effects Special situations -Pregnancy and breast feeding -Fistulizing disease -Rescue Therapy and Dual Therapy -Post op treatment of Crohn s Biologic Therapy including newer molecules The Agents Infliximab Adalimumab Certolizumab Natalizumab Verdolizumab Golimumab Ustekinumab Classes TNF alpha Integrins IL 12/23 Worth Mentioning Stem Cell Transplant Fecal Transplant Hyperbaric Oxygen Supplements and Helminths Acupuncture Statins Thalidomide Etc etc etc Comprehensive IBD Management Treat Complications Treat inflammation 2

3 Traditional Treatment Strategies Top-down Strategy Early, aggressive use of biologic as initial treatment Induces rapid clinical response May enhance quality of life Biologics Immune Suppressors Azathioprine 6-MP Anti-inflammatory Drugs Aminosalicylates Corticosteroids Early Assessing Disease Clinical Assessment Endoscopy Labs Radiology Bottom-up" Strategy Standard, sequential treatment for remission and maintenance Cost-effective Minimal side effects Surgery Surgery Biologics Late Severe PATHOLOGY Immune Suppressors Azathioprine 6-MP Corticosteroids Moderate Anti-inflammatory Drugs Aminosalicylates Corticosteroids Mild Clinical Assessment Age of patient < 40 years Distribution of Disease Clinical/Endoscopic/Radiological Severity of Disease Previous Behavior Smoking Endoscopic Assessment Crohn s Ulcerative Colitis 3

4 Labs CRP, ESR,Platelets,RDW Fecal Calprotectin Fecal Lactoferrin Albumin ASCA and ANCA Radiology CT Enterography MR Enterography Small Bowel Follow Through Newer markers *I2 - Pseudomonas fluorescens *OmpC =outer membrane porin C of E. coli and flagellin have also been described in CD *Pancreatic antibodies - CD > UC patients Clarke K et al ; Dig Dis Sci Sep;53(9): Clarke K, Hashash JG, Swoger JM, et al; Int J Colorectal Dis.2014 Jan;29(1):133 Joossens S et al ; Gastroenterology 2002; 122; Clinical Phenotype What is the Evidence? Aggressive Disease Age < 40 Smoking in CD Perianal Disease Jejunal Crohn s Upper GI Crohn s Multiple surgeries Destructive Disease Steroid Dependent Special Circumstances Persistent Extra Intestinal manifestations Post operative CD Pregnancy 4

5 Biologic Therapy Infliximab Chimeric IgG1K monoclonal Ab Neutralizes biological activity of 2002 (1998) for CD UC-2005 IV Route *Moderate to severe Crohn s Disease and UC *Other indications in IBD Adalimumab Human derived, genetically engineered Anti 2007 for moderate to severe Crohn s UC-2012 Sub cutaneous route Adalimumab UC Week 8 :-16.5 % versus 9.3 % (p=0.019) Week 52:- 17.3% versus 8.5 % (p=0.004) ADA160/80 was safe and effective for induction of clinical remission in patients with moderately to severely active ulcerative colitis failing treatment with corticosteroids and/or immunosuppressants. Ultra 1 and Ultra II Crohn s Double -blind treatment with placebo, adalimumab 40 mg every other week, or adalimumab 40 mg weekly through week 56 Crohn's Disease Activity Index score <150 at weeks 26 and 56. Among patients who responded to adalimumab, both adalimumab eow and weekly were significantly more effective than placebo in maintaining remission in moderate to severe CD through 56 weeks CHARM TRIAL Combel et al ; Gastroenterology 2007 Infliximab UC 364 patients; Drug vs Placebo 5 mg or 10 mg/kg IV ACT I > 60 % vs 37 % : treatment vs placebo ACT II > 60 % vs 29 % : treatment vs placebo Patients treated with induction and maintenance are more likely to have a clinical response at weeks 8, 30, and 54 than were those receiving placebo Active Ulcerative Colitis Trials : Rutgeerts et al NEJM May 2006 Crohn s 58% response to single infusion at 2 weeks Week 30 remission rates 21 % placebo 39% at 5mg/kg dose 45 % at 10 mg/kg dose Treated pts at intervals of every 8 weeks are more likely to be in remission, maintain response and discontinue steroids ACCENT 1 Hanuer et al Lancet

6 #Vedolizumab was not more effective than placebo in inducing clinical remission atweek 6 among patients with CD in whom previous treatment with TNF antagonists had failed. # The therapeutic benefits of vedolizumab in these patients were detectable at week 10. *Moderate/ high quality data-> from four studies: vedolizumab >placebo for induction of clinical remission and response and endoscopic remission in patients with moderate to severely active ulcerative colitis and prevention of relapse in patients with quiescent ulcerative colitis. * Moderate quality data from one study suggests that vedolizumab is superior to placebo for prevention of relapse in patients with quiescent ulcerative colitis. Adverse events appear to be similar to placebo. Dual Therapy Biologic therapy with thiopurines Biologic therapy with methotrexate -Decrease immunogenicity? -Better results in treatment naïve Crohn s Disease -More recent results suggest benefit in UC when low dose thiopurine added to infliximab Sands BE, Feagan BG, Rutgeerts P et al ; ; Gastroenterology.2014 May 21 Bickston SJ, Behm BW, Tsoulis DJ, et al;cochrane Database Syst Rev.2014 Aug 8 SONIC trial moderate to severe Crohns No prior biologic or thiopurine treatment 3 groups RESULTS *Corticosteroid id free clinical i l remission i at 26 weeks: 57% vs 44% vs 30% *Mucosal healing at week 26 44% vs 30% vs 17% Pregnancy and Breast Feeding Breast feeding not an issue Pregnancy -Safe (Category B) -Stop adalimumab and infliximab in 3 rd trimester -Resume post partum -Can continue Certolizumab Mahadevan et al; Gastroenterology 2008 Kane et al ;Infl Bowel Dis Colombel et al; SONIC group NEJM;

7 Post Operative Crohn s Infliximab/Adalimumab prevents post op recurrence CDAI does not correlate with endoscopic recurrence No increase in adverse events Endoscopic assessment within 1 year Prevent trial Clinically phenotype patients Regueiro et al ; Gastroenterology Feb;136(2): Regueiro et al ; Inflamm Bowel Dis Jan;17(1): Clarke k, Regueiro M, Gastroenterol Hepatol 2009 Other Alternatives Helminthic therapy (worms) UC and CD Initial promise for symptom control and healing inflamed tissue The worms are on their last legs!!! Curcumin, extract from turmeric Pilot study > UC and CD patients: ASA dosage reduction in UC patients t and symptomatic ti improvement in CD patients t 1 Large trial in quiescent UC: 2 relapses in treated group versus 8 in ASA only group within 6 month treatment period 2 Larger scale prospective studies needed Fish oil supplements containing omega 3 fatty acids 3 May reduce pain and inflammation when added to standard therapy Results are inconsistent, no clear recommendation Holt, et al. Dig Dis Sci. 2005; 2. Hanai, et al. Clin Gastroenterol Hepatol. 2006; 3. Feagan, et al. JAMA Should/Can we stop Rx Duration of treatment not clearly resolved(side effects/costs) Very Deep Remission -CDAI<150 + Endoscopic Remission Role of persistent mucosal inflammation / risk of cancer Dual vs Single therapy Duration of treatment 30% relapse at 1 year; 50 % at 3 years Clarke k, Regueiro M; Inflamm Bowel Dis.2012 Jan;18(1):

8 Practical Points. Treatment choices should not be generic Aggressive Disease warrants early aggressive treatment -Severe UC -Destructive Crohn s -Steroid Dependent Disease The traditional models are not universally applicable Patients may require surgery prior to starting these treatments Side effects are similar across the class and not daunting Practical points :- Assess disease severity with all available options Clinically phenotype disease Patient circumstances Insurance Compliance-Self injections vs Infusions Patient preferences Golimumab studied in treatment naïve patients No head to head studies Dual therapy shown to be superior in CD Concerns about these agents Lower threshold for the newer therapies. 8

9 Adverse Events Associated with anti-tnf Treatment Risk of Developing non-hodgkin s Lymphoma Patient receiving Immunomodulator +/- anti-tnf Therapy for 1 year Risk without of lymphoma medication with immune suppression Event Estimated Frequency Stop therapy due to adverse event 10% Infusion or injection site reactions 3%-20% Drug related lupus-like reaction 1% Serious infections 3% Tuberculosis 0.05% (5/10,000) Non-Hodgkin s lymphoma (combo) 0.06% (6/10,000) Multiple sclerosis, heart failure, serious liver injury Case reports only Siegel CA. The risks of biologic therapy for inflammatory bowel disease. In Bernstein, ed. The inflammatory bowel disease yearbook, volume 6. In press; Infliximab package insert; Vermeire Gastro 2003; Cush, Ann Rheum Dis 2005; Lenercept study group, Neurology 1999; ATTACH trial 2003 Solid Tumors and anti-tnf Treatment National Data Bank for Rheumatic Diseases ( ) 13,000 patients enrolled, 49% received biologics Type of Cancer Odds Ratio All cancers (0812) ( ) All solid tumors 1.0 ( ) Colon 0.8 ( ) Lung 1.1 ( ) Breast 0.9 ( ) Pancreas 0.5 ( ) Melanoma 2.3 ( ) Non-melanoma skin 1.5 ( ) Wolfe, Arthritis and Rheumatism 2007;56:2886. Risk of NH Lymphoma with anti-tnf + IM treatment for Crohn s Disease Meta-analysis Results 8905 patients representing 20,602 pt-years of exposure 13 Non-Hodgkin s lymphomas Mean age 52, 62% male 10/13 exposed to IM* (really a study of combo Rx) NHL rate per 10, per 10,000 pt-years SIR 95% CI SEER all ages IM alone Anti-TNF + IM vs SEER Anti-TNF+ IM vs IM alone Siegel et al, CGH 2009;7:874. *not reported in 2 9

10 THANKS! Questions?????? 10