Disease Management Strategies for Moderate to Severe IBD in Adults Alyssa Parian, MD Assistant Professor of Medicine Johns Hopkins University April 21, 2016 Outline Overview of IBD Treatments (Benefits/Risks) Benefit of top down therapy Combination therapy Personalized IBD management New and emerging drugs for IBD Preventative care 1
IBD Overview Chronic inflammatory condition of the GI tract affects up to 1.6 million persons in the US and has been rising each year Includes Crohn s disease (CD) and ulcerative colitis (UC) Typically diagnosed between ages 15 35 Second peak from 50 70 Predisposing factors: Genetics Microbiome Triggers GI infections, NSAIDs, antibiotics 3 INFLAMMATORY BOWEL DISEASES 2
IBD Overview Approximately 1.6 million Americans have IBD ~ 780,000 with Crohn s ~ 907,000 with UC There are 70,000 new cases of IBD diagnosed in the US each year ~ 33,000 new cases of CD per year (10.7 per 100,000 people) ~ 38,000 new cases of UC per year (12.2 per 100,000 people) 5 ULCERATIVE COLITIS AND CROHN S DISEASE 3
4/8/2016 Symptoms of UC Bloody diarrhea Passage of mucus Rectal urgency Abdominal cramping Weight loss, fever, anemia Up to 40% will require colectomy ENDOSCOPIC SPECTRUM OF SEVERITY 4
Symptoms and Signs of Crohn s Disease** Crampy abdominal pain Diarrhea - chronic, nocturnal, occasionally bloody Abdominal mass Fever Malnutrition Fatigue Anemia Growth delay Weight loss ** Based on location of Crohn s disease which is different in each patient Crohn s Disease Distribution Ileal Crohn s disease Ileocolonic Crohn s disease Colonic Crohn s disease Upper GI Crohn s disease Perianal Crohn s disease (up to 30% of patients) 5
Crohn s disease Chronic inflammatory disorder of the entire gastrointestinal tract Traditionally, up to 75% of patients will require at least 1 surgery There is no cure patients generally need to stay on medication indefinitely Loftus et al. Gastroenterology. 2004;126:1504-1517. Extra Intestinal Manifestations Associated with colonic disease Peripheral arthritis, EN, and episcleritis are related to the activity of the colitis Ankylosing spondylitis, sacroiliitis, and PSC are independent of disease activity PG & iritis may or may not be related to the activity of IBD DVT/PE 6
Primary Sclerosing Cholangitis SCLEROSING CHOLANGITIS 70 80% of PSC patients have IBD (mostly UC) 2 7% of UC patients have PSC Mild colitis Very high risk of colon cancer persists after liver transplantation High risk of pouchitis after TPC IPAA TREATING IBD 7
Medical Therapy in IBD Currently there is no cure for Crohn s The only cure for ulcerative colitis is taking out the colon All but the patients with the mildest of disease will need to be on chronic lifelong therapy Goals of therapy: Induce and maintain a clinical remission Minimize steroid exposure Avoid complications of the disease Achieve a good quality of life Minimize short and long term toxicity Medications in IBD Benefits and Risks 8
Medication Classes 5 aminosalicylic acid agents Steroids Thiopurines Anti TNF agents Vedolizumab New and Emerging Therapies FDA approval table Crohn s Disease Induction mild to moderate budesonide Induction and maintenance moderate to severe infliximab, adalimumab, certolizumab pegol, natalizumab, vedolizumab Ulcerative Colitis Induction mild to moderate budesonide MMX Induction and maintenance mild to mod 5 aminosalicylic acid Induction and maintenance mod to severe infliximab, adalimumab, golimumab, vedolizumab 9
5 aminosalicylic acid (5 ASA) Well tolerated Can be a high pill burden (leading to noncompliance) Induction and maintenance of remission of mild moderate UC Available rectally for L sided disease Effective for UC, mixed data for colonic CD Requires yearly creatinine surveillance Rarely causes Pancreatitis Renal insufficiency Paradoxical worsening of diarrhea 5 ASA Formulations Lialda: 4 pills once a day (best compliance) Apriso: 4 pills once a day (best compliance) Asacol: 2 capsules 3x/day Pentasa: coated microgranules which release in the small and large bowel (CD + UC); 2 capsules 4x/day 10
5 aminosalicylic acid (5 ASA) Multiple formulations for 5 ASAs: Delzicol: 2 pills 3x/day Colazal: 3 pills 3x/day; low and variable bioavailability; higher risk of diarrhea Dipentum: 2 pills 4x/day; highest risk of diarrhea Sulfasalazine: 2 pills 4x/day; contains sulfa, higher likelihood of allergic reaction leading to rash, fever, hepatic dysfunction; decrease sperm production in men; can also treat rheumatologic disease Corticosteroids Effective in the induction, but NOT maintenance of remission in both CD and UC Two common oral formulations: prednisone and budesonide Budesonide has high first pass metabolism in the liver therefore minimizing the side effects of the steroid ($$$) Steroids in CD are associated with increase in infections, penetrating disease, surgery and death 11
Potential Adverse Effects to Steroids Glaucoma Cataracts Infection Osteoporosis Avascular Necrosis Myopathy GI upset Nausea Diabetes Palpitations Hypertension Fatty liver Swelling Moon facies Abdominal striae Easy bruising How to best use steroids in IBD Minimize the dose and duration as much as possible especially in CD Consider budesonide formulations: Entocort: releases in the distal ileum/cecum for ileocolonic Crohn s disease Uceris: releases throughout the colon for UC Concomitant calcium + Vit D during steroid courses Consider GI protection with H2 blocker or PPI 12
Thiopurines (6MP, Azathioprine) Steroid sparing oral agent Effective in maintaining remission in ~ 50% of CD and UC patients MAINTENANCE of steroid induced remission Can take up to 3 months to be fully effective TPMT activity level (phenotype) To identify poor metabolizers who have a high rate of severe cytopenias Thiopurines RISKS (6MP, Azathioprine) Potential reactions / adverse events Low white blood cell count Increased risk for infection Increased risk for lymphoma About 4 5 times over the general population Elevated liver function tests Pancreatitis (3%) Non melanoma skin cancers Fatigue Need close blood monitoring Especially important when medication is first started Overall, about 10% of patients will need to stop the medication because of a reaction or adverse event 13
Anti TNF Agents Infliximab, adalimumab, certolizumab*, golimumab** Using biologic therapy earlier in Crohn s disease Most effective for perianal fistulizing disease For steroid refractory ulcerative colitis Need negative TB screen and negative hepatitis B sag prior to starting Increases risk for: Infections Infusion/injection reactions Loss of response (up to 50%)?Lymphoma?Skin cancers * Approved for CD only ** Approved for UC only Anti TNF Agents Infliximab appears to be better than adalimumab In moderate to severe ulcerative colitis In fistulizing Crohn s disease Infliximab is an IV infusion whereas, adalimumab, certolizumab and golimumab are home injections Home injections are associated with a lower healthcare cost, however compliance with treatment cannot be as closely monitored. 14
Vedolizumab FDA approved May 2014 for CD and UC Selective Ab to α4β7 integrin Targets leukocyte trafficking in GI tract Cousin of natalizumab (but doesn t affect CNS) GEMINI I (UC) & II (CD) Trials All patients had active moderate to severe disease About 50% had prior anti TNF exposure Vedolizumab (Anti Alpha 4 Beta 7 Integrin) For Moderately to Severely Active Ulcerative Colitis: Results at Week 6 in 374 Patients P<0.001 P=0.0012 P=0.0009 Feagan et al. N Engl J Med 2013;369:699 710 15
Vedolizumab (Anti 4 7Integrin) For Maintenance of Response in Moderately to Severely Active Ulcerative Colitis: Results at Week 52 in 373 Patients Feagan et al. N Engl J Med 2013;369:699 710 Safety of Vedolizumab No reports of PML 16
Vedolizumab for UC Can consider for moderate UC disease; however for severe disease still using infliximab plus thiopurine Primary non responders of anti TNF Secondary non responders of anti TNF Consider use in elderly patients that are at higher risk for infections Consider use in patients with prior malignancy when anti TNFs are contraindicated No role for acute hospitalized patient due delayed onset of action Further studies needed infliximab vs. vedolizumab in UC Vedolizumab (Anti Alpha 4 Beta 7 Integrin) For Moderately to Severely Active Crohn s Disease: Results at Week 6 in 368 Patients Induction ITT Population Patients, % 35 30 25 20 15 P=0.02 14.5 P=0.23 25.7 31.4 Placebo VDZ 10 6.8 5 0 Clinical Remission CDAI 100 Response 95% CI: Δ 7.8 1.2, 14.3 Δ 5.7 3.6, 15.0 Sandborn W. N Engl J Med 2013 17
Vedolizumab (Anti 4 7Integrin) For Maintenance of Response in Moderately to Severely Active Crohn s Disease: Results at Week 52 in 461 Patients Patients, % 50 45 40 35 30 25 20 15 10 5 21.6 ** 39.0 ** 36.4 Maintenance ITT Population 30.1 * 43.5 ** 45.5 15.9 * 31.7 * 28.8 0 Clinical Remission CDAI 100 Response CS Free Remission Durable Remission Δ17.4 Δ14.7 Δ13.4 Δ15.3 Δ15.9 Δ12.9 Δ7.2 Δ2.0 *P<0.05 **P<0.01 CS tapering began in responders at 6 weeks; for others, as soon as a clinical response was achieved. 14.4 21.4 Placebo VDZ Q8wk VDZ Q4wk 16.2 Sandborn W. N Engl J Med 2013 Vedolizumab for CD Very slow response not until about 10 12 weeks Consider for anti TNF primary and secondary nonresponders Given its excellent safety profile, has largely replaced role of natalizumab No data on fistulizing Crohn s yet Data on post op CD patients expected in the next few months 18
Step up vs. top down therapy Benefits of Top Down Therapy Modify the natural progression by halting inflammation early in disease course Aggressive therapy at earlier stages improves clinical outcomes and increases likelihood of mucosal healing Biologics appear to be more effective when given early in disease course Dual therapy (infliximab & 6MP) > monothearpy Top down therapy for patients with more severe disease and unfavorable disease course 19
Benefits of Top Down Therapy Mucosal healing IBD patients who achieved mucosal healing required fewer hospitalizations, surgeries and ICU admissions There is an improved quality of life Decreased risk of relapse Decreased risk of colorectal cancer Top down Therapy Need to weigh the benefits and risks of combination therapy Determine who will have an aggressive course with complications and need for early surgery Earlier age at diagnosis Early need for surgery Early penetrating/fistulizing disease Presence of anti microbial antibodies In the future, we will be able to better predict on the basis of clinical, genetic, and laboratory factors 20
Combination Therapy Anti TNF agent (infliximab, adalimumab, certolizumab, golimumab) PLUS immunomodulator (thiopurine or methotrexate) The addition of immunomodulator decreases the immunogenicity of the anti TNF agents and decreases the risk of antibody development and secondary non response Combination Therapy in Crohn s The SONIC Trial Steroid Free Remission Week 50 Percent of patients (%) 100 80 60 40 20 0 All Randomized Patients (N=508)* p<0.001 p=0.025 p=0.002 55.6 39.6 28.2 48/170 67/169 94/169 AZA + placebo IFX + placebo IFX+ AZA Rutgeerts P et al. N Engl J Med. 2005;353:2462 2476. 21
Combination Therapy in UC The SUCCESS Trial Panccione R, et al. DDW 2012, abstract #835 Combination Therapy Risks Double immunosuppressed Highest risk for lymphoma, skin cancers Concern for hepatosplenic T cell lymphoma in young men Can consider use of methotrexate instead of thiopurine However if disease is severe and aggressive, the benefits do outweigh the risks and one medication could be stopped after resmission achieved. 22
Personalizing Treatment In IBD Serum Biomarkers Associated with IBD Antibody Antigen IBD phenotype ASCA Saccharomyces cerevisiae Stricturing or penetrating small bowel Crohn s disease and increased need for surgery panca Anti-ompC Anti - 2 Anti-Flagellin NOD2/CARD15 Histone H 1, bacterial antigen? E. Coli Pseudomonas fluorescens cbir Possible increased risk for pouchitis in UC patients Internal perforating, stricturing Crohn s disease, increased need for surgery Stricturing Crohn s disease, small bowel disease, surgery Aggressive small bowel disease Ileal CD location, no behavioral association 23
Drug Level Monitoring Thiopurines TPMT levels are drawn prior to initiating therapy to look for poor metabolizers who have a high risk of life threatening cytopenias Azathioprine/6 MP have levels that can readily be measured 6 TGN is the active metabolite with levels 250 400 therapeutic 6 MMP are the toxic metabolites < 5700 to avoid hepatotoxicity Can use allopurinol to shunt the metabolism towards active drug and away from toxic metabolites 24
Drug Level Monitoring Anti TNFs Reference Study Design N Anti- TNF Drug Level Monitoring Subanalysis Li, 2010 CLASSIC I/II Karmiris, 2009 Prospective Mazor, 2013 Retrospective Subanalysis Sandborn, PRECISE 2012 (open-label) Roblin, 2014 Sandborn, 2014 Sandborn, 2014 Crosssectional Prospective PURSUIT Prospective PURSUIT 258/C D ADL Clinical Impact of Serum Anti-TNF and Drug Level Week 4 serum TL predicted clinical remission in CLASSIC I but no doseexposure-response relationship identified in CLASSIC II 168/C D ADL Low serum TL predicted LOR Serum TL >5 μg/mL associated with 121/C higher clinical remission rates and D ADL normal CRP 203/C D CZP 40 CD/U C ADL 625/U C GOL 157/U CGOL Drug plasma concentrations positively correlated with clinical remission Higher serum TL (median 6.5 μg/mL) associated with clinical remission and mucosal healing Drug concentration quartile at week 6 positively predicted improvement in Mayo score and rates of clinical response and remission Drug concentration quartile positively predicted higher rates of clinical remission 25
Drug Level Monitoring Anti TNF Fecal Calprotectin is Elevated with Increased Mucosal Inflammation in UC Fecal calprotectin μg/ml Endoscopic activity Clinical activity index # of patients Mean ± SD Range Mean ±SD Range Remission (0 4) 26 34 ± 29 9 132 1.9 ± 1.6 0 7 Mild (5 10) 41 309 ± 287* 15 1148 6.4 ±3.4* 1 12 Moderate (11 17) 46 480 ± 309 # 43 1436 8.8 ±2.9 # 3 12 Severe ( 18) 21 807 ± 232 418 1371 11.3 ±1.3 8 12 * P<0.01 btwn remission and mild; # P<0.01 btwn mild to moderate; P<0.01 btwn moderate to severe SENS (%) SPEC (%) PPV (%) NPV (%) Accuracy (%) Calprotectin 50μg/g 93 71 91 81 89 Calprotectin 100μg/g 86 88 96 65 86 Clinical activity index 5 81 52 84 47 73 CRP 5mg/L 60 67 84 37 62 WBC 7.9 g/l 59 62 82 34 60 Schoepfer et al. Inflamm Bowel Dis. 2009;15:1851 8. 26
New & Emerging IBD Therapies UC Upcoming Drugs Etrolizumab Subcutaneous, binds β7 subunit of both α4 β7, αe β7 Phase III Tofacitinib Oral janus kinase 1 and 3 inhibitor Phase III completing Approved for use in psoriasis Ozanimod Oral sphingosine 1 phosphate receptor inhibitor Phase II complete* Selectively retains activated lymphocyte in lymph node Fingolimod approved for MS 27
CD Upcoming Drugs Ustekinumab IL 12/23 inhibitor completing phase III Mongersen oral SMAD7 inhibitor phase III underway MANAGING IBD: PREVENTATIVE CARE 28
AGA IBD QI Measures 2012 PQRS 1. Document disease activity and severity 2. Recommend steroid-sparing therapy after 60 days 3. Assess bone health if steroid-exposed 4. Recommend influenza vaccine 5. Recommend pneumococcal vaccine 6. Document recommendation for cessation of smoking 7. Assess for HBV status pre-anti-tnf 8. Assess for latent TB pre-anti-tnf www.gastro.org/practice/quality-intiiatives CCFA Process Measures Highlights Test for TB before anti TNFa therapy Test for C. difficile in flares Flex sig. for CMV in steroid refractory hospitalized UC Check TPMT before starting thiopurines Recommend steroid sparing agents if >4m steroids Recommend colectomy or close surveillance for low grade dysplasia in colitis Recommend smoking cessation if smoker with CD Educate patients regarding vaccinations Melmed, et al. Inflamm Bowel Dis, accepted 2012. 29
Risks of Colon Cancer in IBD Longer duration of disease Greater extent of disease Increased activity of disease 1,2,3 Family history of CRC 4,5 Primary sclerosing cholangitis 6 Younger age of diagnosis (?) Stricture Pseudopolyps 1.Rutter M et al. Gastroenterology. 2004;126:451. 2. Gupta R et al. Gastroenterology. 2007;133:1099. 3.Rubin D et al. Gastroenterology. 2006;130:A2. Abstract 14. 4. Askling J et al. Gastroenterology. 2001;120:1356. 5. Rubin DT et al. Gastroenterol Clin N Am. 2006;35:581. 6. Lindberg BU et al. Dis Colon Rectum. 2001;44:77. IBD Colorectal Cancer Screening After 8 years of colitis involving at least 1/3 of the colon colonoscopy every 1 2 yrs PSC + UC begin screening yearly at diagnosis Proctosigmoiditis doesn t increase the risk of CRC 30
Smoking and Crohn s disease Increases risk of small bowel Crohn s disease Increased risk of penetrating or stricturing Crohn s disease Makes CD medications less effective Increases risk of additional surgery Ryan et al. Am J Surg. 2004;187:219-225. DVT Prophylaxis in IBD Patients IBD patients have increased risk of venous thromboembolisms (VTE) IBD flares further increase the risk of VTE VTE prophylaxis has been shown to be safe even in patients with bloody diarrhea due to IBD 31
IBD Preventative Care Osteoporosis screening: postmenopausal ongoing corticosteroid treatment cumulative use of steroids > 3 mos history of low trauma fractures age > 60 years Osteoporosis prevention: If anticipated steroid course > 3 mos, calcium 1200 mg/d and vit D 800 mg/d Conclusions IBD is a complex, heterogenous condition that affects patients for many decades The exact pathogenesis is still unknown There is no cure and patients typically require life long therapy Each therapy has its own risks and benefits that need to be carefully weighed for each patient New therapies continue to be developed with the eventual hope for a cure 32
Questions? Alyssa Parian aparian1@jhmi.edu 33