Crohn's Disease. The What, When, and Why of Treatment

Transcription

1 Crohn's Disease The What, When, and Why of Treatment Brian Feagan, MD, FACG Professor of Medicine and Epidemiology and Biostatistics Director, Robarts Clinical Trials Robarts Research Institute University of Western Ontario London, Ontario, Canada In my lecture today, I will be discussing off label use of several medications to treat Crohn s disease 1

2 Diane 32 year old female with no significant PMH presents with 3 months of abdominal pain, diarrhea, 20 pound weight loss with blood in stool for past 3 weeks No recent travel or antibiotics FH: Father has Crohn's disease SH: Smokes ½ ppd for 10 years 3 Diane PE: Well appearing female in NAD, remainder of exam unremarkable except for minimal abdominal tenderness Stool samples for enteric pathogens negative Colonoscopy: Moderate Crohn's ileocolitis with deep serpigenous ulcerations in the ileum, ascending and transverse colon with patchy left sided colitis CTE: Thickened distal ileum and colon with hyperemia of the intestinal wall in the ileum, right and transverse colon Labs WBC 13.5K Hct 30% MCV 80 Platelets 600K Albumin 2.9 g/dl (nl > 3.6) CRP 8 mg/dl (nl <1.0) Ferritin 21 (nl >20) 4 2

3 Diane 5 Diane: Treatment Options 1. Advised to stop smoking 2. 5 ASAs 3. Antibiotics 4. Steroid induction and antimetabolite 5. Steroid induction and anti TNF agent 6. Steroid induction and both antimetabolite and anti TNF agent 7. Anti TNF +/ antimetabolite 6 3

4 Conventional CD Therapy is Sequential Mild Moderate Severe Aminosalicylates TNF antagonists Antibiotics Locally Active Oral Corticosteroids Oral Corticosteroids Antimetabolites (AZA,6 MP, MTX) Parental Corticosteroids Bowel Rest Natalizumab Surgery 7 Most Crohn s Disease Patients Will Require Surgery % Patients Years After Onset Mekhjian HS, et al. Gastroenterology. 1979;77(4 Pt2):

5 Mortality in Crohn s Disease Survival is modestly reduced (6 7% over 20 years) Females diagnosed before the age of 50 Disease related complications, gastrointestinal cancer Jess T, et al. Gastroenterology. 2002;122(7): Can Early Use of Highly Effective Therapy Alter Natural History of CD? Disease Complications Natural Course Years Induce and maintain gastrointestinal healing Prevent strictures and penetrating complications Prevent extraintestinal complications Decrease hospitalization and/or surgery Decrease long term cost of care 10 5

6 Kaplan-Meier CD-Related Hospitalization: CHARM CD related Hospitalization Risk (%) Week 2 Placebo Adalimumab Days since randomization n=778 randomized to adalimumab (ADA) 40 mg EOW or weekly, or placebo, through 56 weeks 3 month Hospitalization Risk Placebo (%) 7.3 ADA (%) 1.6 (RR reduction: 78%) 12 month Hospitalization Risk Placebo (%) 13.9 ADA (%) 5.9 (RR reduction: 57%) Feagan BG, et al. Gastroenterology. 2008;135(5): Crohn s Disease Validated Predictors of Risk 6

7 Predictors of Rapid Progression to Surgery Factor Odds Ratio (95% CI) Current smoker 3.1 ( ) Abdominal pain 1.8 ( ) Nausea/vomiting 2.1 ( ) Ileal localization only 2.2 ( ) Oral steroid use in 1 st 6months 3.8 ( ) Sands BE, et al. Am J Gastroenterol. 2003;98(12): Predictors of Disabling Disease Factor Odds Ratio (95% CI) Initial requirement for steroids 3.1 ( ) Age less than ( ) Perianal disease 1.8. ( ) Beaugerie L, et al. Gastroenterology. 2006;130(3):

8 Outcomes of Corticosteroid Therapy for CD Immediate Outcome (n=74) Complete Remission 58% (n=43) Partial Remission 26% (n=19) No Response 16% (n=12) 1 Year Outcome (n=73) Prolonged Response 32% (n=24) Steroid Dependent 28% (n=21) Surgery 38% (n=28) Steroid use is a risk factor but 50 % of patients in the community never see steroids! Faubion WA, et al. Gastroenterology. 2001;121(2): Prognosis of CD Patients with Severe Ulcerations Retrospective cohort 102 patients with active CD Severe endoscopic lesions (SEL) defined as deep ulcerations >10% of mucosal area with at least one colonic segment Risk of colectomy associated with SELs, high CDAI, absence of immunosuppression % Colectomy No SEL SEL 62% 42% 31% 18% 6% 8% Years Allez M, et al. Am J Gastroenterol. 2002;97(4):

9 Risk of Progression and Positive Serology Anti I2, anti OmpC, anti CBir1, ASCA 1 Anti-outer membrane protein C (anti-ompc) Anti-CBir1 flagellin (anti-cbir1) Anti-Saccharomyces-cerevisiae (ASCA) ) Probability of Nonprogressive CD P=0.03 N=97 N=70 All Negative (0/3) >1 of 3 positive Time to Disease Progression (months) Dubinsky MC, et al. Am J Gastroenterol. 2006;101(2): Crohn s Disease Effective Combination Therapy? 9

10 Infliximab/AZA in Steroid- Dependent CD Remission % 100% 80% 60% 40% 20% P< % 75% P= % 57% Placebo (n=58) Week 0,2,6 + AZA/MP Infliximab (n=57) 5mg/kg Week 0,2,6 +AZA/6 MP P=> % 40% 0% Week 12 Week 24 Week 52 Lemann M, et al. Gastroenterology. 2006;130(4): Early Combination Therapy vs Conventional Management of CD Newly diagnosed, antimetabolite, anti TNF, or steroid naïve CD patients (n=133) + AZA MTX Steroids + IFX IFX (0,2,6 weeks) + AZA + (Episodic) IFX Steroids Steroids Conventional therapy (n=66) Early aggressive (n=67) D Haens G, et al. Lancet. 2008;371(9613):

11 Management of CD: Step Up vs. Top Down D Haens G, et al. Lancet. 2008;371(9613): Early Combination Therapy vs Conventional Management of CD Patients in remission without steroids and surgical resection (%) 100 * ** Early aggressive (n=65) Conventional therapy (n=64) 0 6 months 12 months *p= **p= D Haens G, et al. Lancet. 2008;371(9613):

12 Early Combination Therapy vs Conventional Management of CD: Ulcer Disappearance Complete endoscopic remission after 2 years of treatment 100 ** (n=26) Early Combined (n=23) Conventional therapy **p=0.003 D Haens G, et al. Lancet. 2008;371(9613): SONIC Study Design Main Extension Visits Week 0* Week 2 Week 6 Week 10 Week 14 Week 18 Week 22 Week 26* Week 30 Week 34 Week 38 Week 42 Azathioprine 2.5 mg/kg + placebo infusions Randomization of Patients Infliximab 5 mg/kg + placebo capsules Primary Endpoint (Corticosteroid free Remission at Week 26) Week 46 Week 50 Secondary Endpoint (Week 50) Week 54 Infusions * Endoscopy performed at Weeks 0 & 26 Colombel JF, et al. N Engl J Med. 2010;362(15): Infliximab 5 mg/kg + Azathioprine 2.5 mg/kg 24 12

13 SONIC Clinical Remission Without Corticosteroids: Week 26 Proportion of Patients (%) p<0.001 p=0.009 p= /170 75/169 96/169 AZA + placebo IFX + placebo IFX+ AZA Colombel JF, et al. N Engl J Med. 2010;362(15): Crohn s Disease Monitor a Validated Surrogate Endpoint? We Don t Have One!? CRP?? Endoscopy?? MRI? 13

14 Early Use of TNF Antagonist in CD Heterogeneous patient population Validated predictors of risk Effective combination therapy Validated surrogate marker Scientific proof of concept Yes Yes Yes No SONIC, Top Down 27 Crohn s Disease Do We Treat Everyone with Early Combined TNF Antagonist Therapy? No! 14

15 Therapeutic Algorithm for Active Luminal CD (Moderate Risk) 5 ASA Antibiotics Re evaluate in 12 wks remission? Yes No Maintenance Therapy GCS (Bud vs Pred depending on disease activity and localization) Yes Taper GCS Without Fistula TNF Antagonist + AZA or MTX (GCS as needed) Evaluate in 4 wks remission? (HBS 4) No No Add TNF Antagonist + AZA or MTX Taper GCS, re evaluate in 12 wks remission? Re evaluate in 12 wks remission? Yes No Continue Combination Increase TNF Antagonist to weekly dose Maintenance Therapy Re evaluate in 12 wks remission? Courtesy of Brian Feagan, MD Yes Continue Combination Maintenance Therapy Yes Continue Combination Maintenance Therapy No Switch Antimetabolite Yes Continue Combination Maintenance Therapy Re evaluate in 12 wks remission? No Switch TNF Blocker Re evaluate in 12 wks remission? No Consider Resection 29 Crohn s Disease Minimizing Side Effects of Steroids, Antimetabolite and Biologic Agents 15

16 Corticosteroid Toxicity Moon face Acne Ecchymoses Hypertension Hirsutism Petechial bleeding Striae Diabetes Infection Osteonecrosis Osteoporosis Myopathy Cataracts Glaucoma Psychosis 31 Azathioprine/6-Mercaptopurine Toxicity Nausea Allergic reactions (fevers, arthralgias) Pancreatitis Bone marrow depression Drug induced hepatitis Infectious complications Lymphoma, non melanoma skin cancer Present DH, et al. N Engl J Med. 1980;302(18):

17 Lymphoma Risk and Thiopurines CESAME cohort 19,486 patients in France with IBD Outcomes based on drug exposure 23 new cases of lymphoproliferative disorders diagnosed HR 5.28 ( ) for lymphoproliferative disorder with thiopurine exposure Beaugerie L, et al. Lancet. 2009;374(9701): Kotlyar K, et al. Am J Gastroenterol. 2010; 105;S Minimizing Methotrexate Toxicity Regular counseling regarding birth control 1 mg Folic acid supplementation daily Monitor CBC, liver enzymes monthly Evaluate risk factors for liver disease Diabetes Obesity Alcohol abuse Liver biopsy no longer recommended Alfadhli A. Cochrane Database Syst Rev. 2005; 25(1):CD

18 Anti-TNF Agents: Adverse Events Immunogenicity Infection Granulomatous (TB, histo, Listeria) Viral, fungal Autoimmunity Lymphoproliferative dx? Neoplasm Skin Pediatric tumors Psoriaform lesions Demyelinating disorders true causal??? Worsen or de novo congestive heart failure Hepatotoxicity (rare) true causal?? Stallmach A, Hagel S, Bruns T. Best Pract Res Clin Gastroenterol. 2010;24(2): Summary Safety Slide Corticosteroids appear to be associated with many adverse events and side effects Patients on antimetabolites need to be monitored for short and long term side effects Biologics can cause immune as well as infectious type of complications Balance risk and benefit for each patient 36 18

19 Diane: Follow-Up Received appropriate vaccinations Normal TPMT enzyme activity Given severity of illness based on laboratory, imaging and endoscopic parameters, she was treated with steroid induction, azathioprine and anti TNF agent Improved and steroids were tapered off by 10 weeks Remains in clinical remission on azathioprine and anti TNF 37 Conclusions Current treatments do not modify the natural history of CD New treatment approaches are needed However, we don t know who to treat, how to follow them, and whether aggressive early treatment is more effective than step care Treating everyone with early combined immunosuppression is not sensible and probably not cost effective 38 19

20 Conclusions, Implications for Practice and Future Directions SONIC, Top Down, COMMIT have told us that combination therapy is superior to conventional management Focus has turned to early use of combination therapy in high risk patients or an accelerated step care Questions remain regarding the optimal induction strategy and the possibility of drug withdrawal New treatment algorithms have the potential to improve patient outcomes and disease course 39 20