Personalized Medicine in IBD Anita Afzali MD, MPH Assistant Professor of Medicine Director, Inflammatory Bowel Diseases Program University of Washington Harborview Medical Center CCFA April 2 nd, 2016
Disclosures Abbvie Consultant, Advisory Board UCB Consultant, Advisory Board Takeda Consultant Janssen Consultant Prometheus Consultant
What is Personalized Medicine?
Personalized Medicine Introduced in the 1970s Provides optimal medical care by using comprehensive pathophysiology-based information Prevent, diagnose and treat disease Custom-made for each individual patient
Right Patient, Right Treatment, Right Time Integration of clinical variables (i.e. age, gender), disease characteristics, genetic and conventional laboratory testing to guide treatment decisions Decrease risk of adverse events and disease complications Potential to optimize efficacy and outcomes
Spectrum of IBD Crohn s Disease Ulcerative Colitis Indeterminate Colitis
Spectrum of IBD Crohn s Disease Ulcerative Colitis Indeterminate Colitis
The -omes in IBD Pathogenesis Taken from Fiocchi C. Dig Dis 2015
Personalized Medicine IBDs are chronic complex diseases with multiple pathogenic components that interact with each other Complexity + interaction = unique molecular pathways only relevant to certain disease subtypes and individuals Not for entire IBD Population
Why do we need Personalized Medicine in IBD?
Exact Etiology Unknown: Inappropriate immune response Genetics Immune System/ Inflammation Environmental Influence Luminal microbial antigens/adjuvants CD=Crohn s disease; IBD=inflammatory bowel disease. Khor B, et al. Nature.2011. Cosnes J, et al. Gastroenterology. 2011.
What is the Immune System? Cells (T cells, B cells, macrophages) that defend the body against attack from infections To eradicate infection, the immune system turns on, causes inflammation Once an infection is eliminated, the immune system knows how to turn itself off Photo courtesy of Scott Plevy, MD
Dysregulated Immune System In IBD, the off switch is broken Inflammation is a Key Aspect of IBD
IBD Medicine Cabinet Over-the-Counter Antibiotics 5-Aminosalicylates/Mesalamine Prednisone, Budesonide Immunomodulators AZA/6MP, MTX Biologics/Anti-TNFs/Anti-Adhesions
Biologics: Protein Target Specific Biologics:Anti-TNFs/Anti-Adhesions New Therapies have and will be designed to Target specific Inflammatory proteins (TNF best example) Genetic defects Microbial imbalances Directly target what is responsible for the disease process the inflammatory cascade
CHRONIC INFLAMMATION: PROTEINS CALLED CYTOKINES ARE THE LIGHT SWITCH TNF IL-1 IL-8 IL-12 IFN IL-4/IL-13 IL-1Ra TGF IL-10 On Off
Anti-TNFs in IBD Infliximab approved for CD 1998 Adalimumab for CD 2002 Certolizumab pegol for CD 2008 Infliximab approved for UC 2005 Adalimumab for UC 2012 Golimumab for UC 2013 Adapted from Curr Opin Rheumat 2014 Fausel R and Afzali A. Ther Clin Risk Manag 2015
Protein Target Specific: Biologics in IBD Revolutionized treatment and management of UC and CD Why do we use them? Very effective Reduces hospitalization, surgery Steroid free remission Improved quality of life Changes the natural history of disease** Limitations: costs, misinformation
Multiple Sclerosis Asthma Crohn s Disease Ulcerative Colitis Psoriasis Rheumatoid Arthritis
Rheumatoid Arthritis IBD TNF
Stages of Rheumatoid Arthritis Early Intermediate Late Courtesy of J. Cush, 2002
Mean change from baseline through 102 weeks Change in Joint Damage Mean through 102 Weeks Anti-TNF 14 Placebo 3 mg/kg qw8 3 mg/kg qw4 10 mg/kg qw8 10 mg/kg qw4 12 10 8 6 4 2 0 p < 0.001 for each infliximab arm vs. placebo at week 30, 54, and 102 Baseline Week 30 Week 54 Week 102
n=19 n=35 n=19 n=35 n=20 n=22 n=20 n=22 n=45 n=55 n=45 n=55 n=131 n=98 n=131 n=98 % in CDAI Response or Remission Response and remission to Anti-TNF by disease duration 100% 90% 90% 80% 70% 60% 50% 40% 30% 37% 68% 37% 75% 50% 55% 36% 62% 36% 47% 29% 57% 33% 44% 24% 20% 10% 0% Sandborn WJ et al. Am J Gastro 2006 Colombel et al, NEJM 2007 <1 Year 1-<2 years 2-<5 years >=5 years Response Remission Placebo Response Placebo Remission PRECISE trial (certolizumab)
Anti-TNF: Endoscopic Healing
We Don t See the Deformities of the Intestines until Complication Early Intermediate Late Courtesy of J. Cush, 2002
Inflammation -> Fistula, Stricture Taken from M. Shaikhani MD
Cumulative Probability (%) THE EVOLUTION OF CROHN S DISEASE: INFLAMMATION LEADS TO DAMAGE 100 80 60 Penetrating 70% 40 20 Inflammatory Stricturing 18% 0 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240 Months Over a 20-year period, 88% risk of developing stricturing (18%) or penetrating (70%) disease Cosnes J et al. Inflamm Bowel Dis. 2002
Natural History Most Crohn s Patients Will Require Surgery Mekhjian HS et al. Gastro 1979.
Patients (%) Natural History Of Ulcerative Colitis n=1161 100 90 80 70 60 50 40 30 20 10 0 0 25 Years after diagnosis Risk of colectomy: 24% after 10 years ~ 30% after 20 years Significant Increased risk of cancer Colectomy Disease activity Remission Adapted from Langholz E, et al. Gastroenterology 1994
Temporal trends of Colectomy in UC Kaplan GG et al. AJG 2012 Since introduction of biologic agents/anti-tnfs, decrease in total colectomy in UC patients
The Right Patient? Which Patients are at highest risk for disease complications? How do we choose the Right Patient for Early Appropriate intervention?
5-Yr Follow up of Crohn s Patients Variable Percent of Patients Non-disabling (n = 166) Disabling (n = 957) Male 40.4 37.3 Independent Risk Factors Odds Ratio (95% CI) 2.1 (P = 0.0004) Age < 40 yr 77.1 87.7 Disease location Small bowel only 44.6 32.8 Small bowel & colon 25.9 39.4 Colon only 29.5 27.8 Smoker 50.3 57.4 Systemic findings 44.6 48.6 Perianal lesions 17.5 26.4 Steroids for first flare 37.3 65.2 1.8 (P = 0.01) 3.1 (P = 0.0001) Beaugerie L, et al. Gastroenterology. 2006 0.5 1 2 3 4 5
Percent Distribution of Patients and PPV of Independent Factors for Disabling CD 100 No factors (score = 0) 1 factor (score = 1) 80 2 factors (score = 2) All 3 factors (score = 3) 91 93 60 40 51 61 67 20 0 31 5 13 Distribution of Patients Positive Predictive Value Beaugerie L, et al. Gastroenterology. 2006
Prognostic Value of Clinical Parameters Mild disease course Older age Higher education level Longer dz duration No smoking No rectal involvement Aggressive disease course Age at diagnosis <40 Perianal dz Weight loss >5kg Smoking Deep colonic ulcers Need for steroid use Extensive small bowel dz Early Appropriate Therapy Vermeire S, et al. Gut 2013
Additional Objective Measures: Associations of Serology and Disease Behavior Small Bowel Fibrostenosis Internal Perforating Surgery UClike Pouchitis ASCA X X X X anti-ompc X X anti-cbir1 X X X X anti-fla-x X X anti-a4- Fla2 X X panca X X Mow WS, et al. Gastroenterology. 2004 Targan SR, et al. Gastroenterology. 2005 Schoefer AM, et al. Inflamm Bowel Dis. 2009
Serology Predicts Progression to Surgery Survival estimates according to serology antibody sum Shortest time to CD-related surgery Dubinsky MC, et al. Clin Gastroenterol Hepatol. 2008
The Right Treatment? If at high risk for disease complications, How do we choose the Right Treatment?
IBD Treatment Strategy Top-down Strategy Early, appropriate use of biologic as initial treatment Induces rapid clinical response May enhance quality of life Step-up" Strategy Standard, sequential treatment for remission and maintenance Cost-effective Minimal side effects Biologics Immunemodulators - Azathioprine/6MP - MTX Anti-inflammatory Drugs Aminosalicylates Corticosteroids Surgery Surgery Biologics Immunemodulators - Azathioprine/6MP - MTX Corticosteroids Anti-inflammatory Drugs Aminosalicylates Corticosteroids Early Late Severe Moderate Mild
Treatment Approach Strategies Low risk of disease progression Top-down : may over-treat and expose patients to costs, risks of immunosuppression High risk of disease progression Step-up : may postpone adequate therapy in aggressive disease and results in disease progression, complications, morbidity
Update in the Evolution of Treatment Goals & Strategies Improved clinical symptoms Clinical remission Mucosal healing Steroid free remission Histologic remission Adapted CCFA Canada Webinar 2015
SONIC Steroid-Free Clinical Remission at Week 50 All Randomized Patients (N=508)* p=0.028 P = 0.028 P p<0.001 < 0.001 p=0.035 P=0.035 41/170 59/169 78/169 * Patients who did not enter the Study Extension were treated as non-responders Colombel JF et al. NEJM 2010
SUCCESS Steroid-Free Clinical Remission at Week 16 Panaccione R et al. Gastroenterology 2014
Combination Therapy in IBD: Use of Aza or MTX Better clinical outcomes Improved response to biologic therapy Decreased risk for antibody development Decreased need for steroids
The Right Treatment and Dose? One size doesn t fit all one dose isn t for all How do we choose the Right Dose?
Pharmacokinetics: How good drug works Factors More Drug Less Drug Males Body size Poor nutrition, albumin High inflammation, CRP X X X X Aza/MTX use X Presence of antibodies High baseline TNF levels Smoking X X X
OPTIMIZING TREATMENT For the Early Appropriate Patient Azathioprine 6-mercaptopurine Anti-TNFs Role of measuring metabolites and drug levels
Pharmacogenomics Using genetics to optimize medical therapy TPMT TPMT mutation Azathioprine 6-MP Azathioprine 6-MP Safe Toxic
Potential Utility of Metabolite Monitoring Identify Reasons for Non-Response 6TGN 6MMP Inadequate dose Non-adherence 6MMP shunting Drug Resistance
A New Era in IBD: Therapeutic Drug Monitoring (TDM) ~50% IBD patients will require dose modification or switch of treatment Symptoms may not be correlated with active inflammation (endoscopy vs CRP) Need to identify patients with Insufficient drug Anti-drug antibodies Causes other than active IBD
CRP mg/l CRP CRP mg/l CRP Association of CRP, ATI, Drug Level 25 20 15 10 5 P=0.0001 IFX_positive 25 20 15 10 5 IFX- IFX+ ATI_positive ATI- ATI+ P=0.0038 IFX- IFX < 3 μg/ml IFX_positive IFX+ IFX 3 μg/ml 52% lower CRP 59% higher CRP ATI- ATI ATI_positive ATI+ ATI+ Higher drug concentration levels associated with lower CRP Higher detectable antibodies associated with higher CRP Feagan B et al. Gastroenterology 2012
Therapeutic Drug Monitoring: Guide to optimize treatment High detectable antibodies Sub-therapeutic anti- TNF drug level Therapeutic drug level, low/no antibodies Change to another anti-tnf Increase dose or frequency of anti-tnf Evaluate by endoscopy/labs/imaging active or inactive disease? Afif W et al. Am J Gastro 2010
The Right Time? Timing is Everything.
Heart Disease
Treat to Target Symptomatic relief is NOT enough Need serial objective evaluation of inflammatory burden: Lab studies: CRP/ESR, Nutrition Endoscopic: colonoscopy, EGD, capsule Mucosal healing Radiologic: CAT or MRI scan Strictures, fistulas
Cumulative Probability (%) Timing for IBD 100 80 60 Penetrating 70% 40 20 Inflammatory Stricturing 18% 0 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240 Months Cosnes J et al. Inflamm Bowel Dis. 2002
Personalized Medicine Who is the Right Patient? What is the Right Treatment? When is the Right Time? The Art of Personalized Medicine in IBD
An Approach to Personalized Medicine First Visit: IBD Panel Serotype Genotype Phenotype What kind of IBD do you have? How will your disease progress? Predict adverse event Patient-specific treatment plan New, Integrated Target-Specific Therapy
Will IBD Medicine Be Personalized? Different pathogenesis, different therapies Genetic mutations Immunologic response to bacteria Clinical Phenotype Treatment NOD2 ASCA SB dz IBD - I A IL-23R Missing bacteria? Altered microbiota Mild SB dz Anti- IBD - II IL-23(?) UC - like IBD III Mild SB dz Probiotic Gene X Anti- CBir1 fistula IBD C IV? Courtesy of S Plevy
UW Medicine Inflammatory Bowel Diseases Program http://www.uwgi.org/ibd/ THANK YOU!