Ulcerative Colitis: State of the Art 2006

Transcription

1 Ulcerative Colitis: State of the Art David T. Rubin, MD Assistant Professor of Medicine Inflammatory Bowel Disease Center University of Chicago Improving Management of Ulcerative Colitis (UC) Better classification/diagnostic schema Optimizing use of existing therapies 5-ASA Corticosteroids Antipurines Anti-TNF Minimizing complications Colectomy Pouchitis Dysplasia/cancer Novel agents for UC Age-Specific Incidence of IBD Rising Incidence of IBD Incidence/1, Population 1 Ulcerative Colitis 1 Crohn s s Disease Per 1, population. Reprinted with permission from Lashner BA. In: Inflammatory Bowel l Disease: A Guide for Patients and Their Families. Philadelphia, PA: Lippincott-Raven Publishers; 1999: Age (year) Incidence has increased dramatically 1.5 in the 195s to ~11. per 1, today Trend continues Rutgeerts P et al. Rev Gastroenterol Disord ;(Suppl 3):S1-S. Vind I, Munkholm P et al. Am J Gastroenterol ;11:17-1. Incidence/1. Inhabitants Incidences of CD and UC and In Copenhagen County vs Crohn's Disease Copenhagen County Ulcerative Colitis Copenhagen County Crohn's Disease Copenhagen County and City Ulcerative Colitis Copenhagen County and City

2 Disease Distribution of Ulcerative Colitis at Presentation UC: Natural History Pancolitis 37% 17% Left-sided UC % Proctosigmoiditis N=111 Percent of Patients 1% 9% % 7% % 5% % 3% % 1% % Years After Diagnosis Colectomy Disease activity Remission Farmer et al. Dig Dis Sci. 1993;3: Percent of patients with disease activity, in remission, or having colectomy performed each year after diagnosis Langholz E et al. Gastroenterology. 199;17:3. Severity of Ulcerative Colitis Modified Truelove and Witts Criteria Clinical Signs of UC Sign/Symptom Bowel movements Mild </d Moderate -/d Severe >/d (mostly bloody) >1 stools/day, continuous bleeding, toxicity, abdominal tenderness/distension, transfusion requirement, colonic dilation on x-ray Temperature ( F)( Weight loss (%) Pulse (beats/minute) Hematocrit (%) ESR (mm/h) Albumin (g/dl) Normal None <9 Normal < Normal >1 >1 >1 <3 >3 <3. < stools/day ± blood Normal ESR No signs of toxicity MILD stools/day Minimal signs of toxicity MODERATE > bloody stools/day + Fever, tachycardia, anemia, or ESR SEVERE FULMINANT Truelove SC, Witts LJ. Br Med J. 1955;:11-1. Kornbluth A, Sachar D. Am J Gastroenterol. ;99:

3 Goals of Management in IBD IBD Diagnostic Considerations Confirm accurate diagnosis Induce remission Defined as absence of inflammatory symptoms, feeling well Maintain remission 95% of patients require maintenance therapies Transition to maintenance occurs after successful induction Need effective and safe long-term therapies Avoid surgery when possible, embrace it when necessary Enhance quality of life Avoid complications of The disease Therapy Left-sided Crohn s s colitis Ischemia Partially treated colitis: patchy disease Disease Progression Rectal sparing in UC Look for clues! Appendectomy protects against UC Smokers have CD Family history usually concordant Andersson RE, et al. N Engl J Med. 1;3: 1. Early Appendectomy Protects Against UC Is it Clostridium difficile? In 5, 1% of patients who developed C. difficile infection had been exposed to antibiotics within the previous months, vs 39% who had no known antibiotic exposure 1 -fold increase in the number of C. difficile cases in last 5 years 1-fold increase in the number of hospitalizations for C. difficile in IBD in last 5 years 5-fold increase in the number of colectomies in IBD patients who are C. difficile positive At IBD Center of the Medical College of Wisconsin, years 3 to 5. Cases of C. difficile in IBD Patients 1 1. Binion DG, et al. Data on file.. Vijayapal AS, et al. Gastroenterology. 5;1(suppl ):A-3. Abstract M IBD Specific Serologic Immune Markers Antibody panca ASCA OmpC Anti-Ι Anti-Flagellin Antigen Histone H 1, bacterial antigen? Anti- Saccharomyces cerevisiae antibody E. Coli Pseudomonas fluorescens CBir 1 Antigen Non-IBD (%) <5% 5% <5% <5% -1% CD (%) 1 5% 55 5% 3 5% 5% 5% UC (%) 5 5% 5% % % %

4 Anti-CBir1 Helps Distinguish Between panca+ Patients Drug Therapies for IBD Anti-CBir1 (O.D.) 3 1 panca + UC P<.1 (level) % 1/5.55 panca + CD % 11/5.3 Aminosalicylates Sulfasalazine Mesalamine Corticosteroids Supportive Olsalazine Prednisone/ agents Antidiarrheal Balsalazide prednisolone Bile Budesonide sequestrants Bulk ACTH formers Antidepressants Pain management Antispasmodics Antibiotics Immunomodulators Metronidazole -MP/Azathioprine Quinolones Methotrexate Rifaximin Cyclosporine Other Anti-TNF Targan SR, et al. Gastroenterology. 5;1:-. UC Treatment Cycle 5-ASA Therapies Disease Activity Diagnosis Treated with 5-ASA 5 (mild to moderate) Adequate maintenance of remission FLARE Complications Treated with steroids CONTINUED FLARES Surgery Cumulative risk of surgery ~3% within 1 years of diagnosis More aggressive steroid therapy, with/without immunomodulator (severe to fulminant) Treated with steroids, with/without immunomodulator (moderate to severe) Disease Activity TAPER Treated with immunomodulator ph-release mesalamine (Asacol ) Time-release mesalamine (Pentasa ) Rectal preparations (Rowasa, Canasa ) Prodrugs (delivery via bacterial azoreductase) Azo-bonded sulfasalazine (Azulfidine) Azo-bonded olsalazine (Dipentum ) Kornbluth A et al. Am J Gastroenterol. : Xu C-T et al. World J Gastroenterol. ;1: Becker JM. Gastroenterol Clinics North Am.1999;: Farmer RG et al. Dig Dis Sci. 1993;3: Azo-bonded balsalazide (Colazal )

5 5-ASA Release Sites Approach to 5-ASA 5 Use in IBD Stomach Small Intestine Large Intestine Pentasa Mesalamine in microgranules Mesalamine w/ eudragit-s Asacol Azo bond Azulfidine Dipentum Colazal Rowasa Canasa Choose drug and route of delivery to maximize dose at location of disease Consider disease and patient variables in customizing therapy Be aware of interpatient variability Encourage adherence to therapy Achieve remission before transitioning to maintenance therapy No evidence to support dose reduction Dose to achieve remission may be dose necessary for durable remission Effective Dosages of Oral 5-ASAs 5 for UC Oral vs Rectal Mesalamine vs Combination Therapy in Active Distal UC N=, weeks AGENT Sulfasalazine Olsalazine Delayed-release mesalamine Mesalamine microspheres Balsalazide INDUCTION (g/d) (note different MW) 1.5, 3 1.,.,.,.75 MAINTENANCE (g/d) 1., 1. 3, % of Patients With Cessation of Bleeding 1 Oral mesalamine (n=) Rectal mesalamine (n=1) Combination (n=) p<.5 vs oral mesalamine 13% 35% % % % 7% 35% 5% Week 1 Week 3 Week 9% Cochrane Database Syst Rev.. 3;:CD53. Safdi M, et al. Am J Gastroenterol. 1997;9(1):

6 % of Patients Improved Assessing the Safety and Clinical Efficacy of a New Dose of Asacol ( mg) ASCEND I 9% % 7% % 5% % 3% 51% 5% Mild+Moderate Population p=ns - primary efficacy population Overall Treatment Success at Week 57% 7% Moderate Population p=.3. g/day. g/day % of Patients Improved Assessing the Safety and Clinical Efficacy of a New Dose of Asacol ( mg) ASCEND II 9% % 7% % 5% % Overall Treatment Success at Week 7% 59% 59% 5% 3% Moderate Population p= primary efficacy population Hanauer SB, et al. Am J Gastroenterol 5; 1:7-5. Mild+Moderate Population p=ns. g/day. g/day % of Patients Improved Assessing the Safety and Clinical Efficacy of a New Dose of Asacol ( mg) ASCEND I+II Treatment Success at Week Pooled Population % 7% % 5% % 3% % 1% % 5% 7% Moderate Population p=.3 5% 53% Mild+Moderate Population p=ns Hanauer SB, et al. Am J Gastroenterol 5; 1:7-5. Hanauer SB, et al. DDW 5 1% 3% Mild Population p=ns. g/day. g/day Maintenance of Remission with Mesalamine: Induction Dose vs Maintenance Dose % Normal at Final Data Capture Maintenance dose < Induction dose % N=3 N=135 N= N=173 Mild UC 5.9% 53.3% 7.% Moderate or Severe UC Outcome measures included maintenance of remission at and 1 months postinduction. Asacol; % rated normal on the physician global assessment of symptom severity (PGA) at final data capture. M=I vs M<I was a significant predictor of final PGA (P<.1, OR=.1, 95% CI= ). Sandborn WJ, et al. Am J Gastroenterol. 5;1(suppl 9):S31. Abstract. Maintenance dose = Induction dose Final Mesalamine Induction Dose. g/day or 3.-. g/day or. g/day

7 Prevalence and Impact of Nonadherence on Outcomes in IBD Corticosteroid Therapy 1.% patients nonadherent 1% of these unintentional Predicted by Disease activity (OR,.55; P =.) New patient status (OR,.1; P =.) Disease duration (OR,.5; P =.1) Patients With Quiescent UC (%) Adherent to 5-ASA 5 therapy Nonadherent to 5-ASA 5 therapy 5 P < Time (months) Study Truelove (5 days) Disease State Severely active Response defined as patients in remission. Steroid/Dose Prednisolone mg (Total n=9) Response (%) Steroid 73 Placebo N/A Sewitch MJ, et al. Am J Gastroenterol. ;99(1 suppl). Abstract. Kane SV, et al. Am J Gastroenterol. 3;9: Truelove SC et al. Lancet. 197;1:17. Corticosteroids: Dependency Short- and Long-term Efficacy Risk of Surgical Resection in Patients With UC After Starting Corticosteroids 1 1-Month Outcomes (n=3) 1-Year Outcomes (n=3) Complete Partial Remission Remission 5% 3% (n=3) (n=19) Prolonged Response 9% (n=31) Steroid Dependent % (n=1) 3 days after initiating corticosteroid therapy. No Response 1% (n=1) Surgery 9% (n=1) % Cumulative Probability Days Faubion W et al. Gastroenterology. 1;11: patients in Olmsted County, MN diagnosed with UC from 197 to Faubion WA Jr et al. Gastroenterology. 1;11:55-.

8 AZA in Severe UC: 1-Year, 1 Placebo- Controlled Trial Results Controlled Trial of AZA in Management of Chronic UC Results Remission Complete Partial Relapse Outcome Withdrawn Side effects Poor compliance Azathioprine n= Placebo n= Mean Total Score 1 1 Total General Health Score First 3 Weeks Last 3 Weeks Prednisone Dose (mg/day) Prednisone Dose First 3 Months Last 3 Months P<.5 Sood A et al. Indian J Gastroenterol. ;19:1-1. Placebo (n=1) Combined scores for the number of bowel movements, state of health, findings on proctoscopy, and rectal biopsy. P<.5 compared to placebo and baseline. Rosenberg J et al. Gastroenterology. 1975;9:9-99. Azathioprine (n=1) Controlled Trial of AZA in Management of Chronic UC Results -Mercaptopurine as Maintenance Therapy for Ulcerative Colitis Mean Activity Score Mean Activity Score at Baseline and Months Placebo n= P=NS.1. AZA n= Comparison between azathioprine and placebo at Months. Kirk A et al. Br Med J. 19;: Prednisone Dose (mg/day) Prednisone Dose at Baseline and Months Placebo n= P<.1..3 AZA n= UC Maintenance Therapy n=3 Probability of remission maintenance 1. George J et al. Amer J Gastroenterol 199; 91: Months

9 AZA vs 5-ASA 5 for Steroid-Dependent, Active UC % of Patients Treatment Success After Months 19% 5-ASA 3. g per day (in 3 divided doses ) P=. 53% AZA mg/kg per day N=7 Defined as clinical remission (Powell-Tuck Index Score of ) and endoscopic remission (Baron Index Score 1) plus steroid discontinuation. Patients treated with concurrent tapering dose of steroids.. g at breakfast and lunch and 1. g at dinner. Ardizzone S, et al. Gut. ;55:7-53. Use of MP/AZA Improves Outcome After Cyclosporin Induction Probability of Avoiding Colectomy 1% % % % % % CSA + MP/aza (n=7) All Patients (n=) CSA alone (n=15) Months Since Initiation of Cyclosporin Cohen, Stein, Hanauer. Am J Gastroenterol 1999;9(): Rationale for TNF Inhibition in UC ACT 1 and ACT : Clinical Response Mucosal TNF immunoreactive cells TNF level in serum TNF level in stool in endoscopically active UC Increased 1 Increased 1, Increased 3 Percent of Patients ACT 1 ACT P<.1 9 P< Weeks 3 Weeks Percent of Patients 1 Weeks 3 Weeks Placebo infusions 5 mg/kg infliximab 1 mg/kg infliximab 1 Murch SH, et al. Gut 1993;3: Komatsu M, et al. Clin Chem 1;7: Nielsen OH, et al. Am J Gastroenterol. 1999;9(1):93-9. Clinical Response Defined as: decrease in the Mayo score by 3% & 3 points AND a decrease in the rectal bleeding subscore of 1 or a rectal bleeding subscore of or 1. Patients with baseline medication were continued on stable doses. For additional information regarding study design, patient population, baseline characteristics, and concomitant medications, please refer to the ACT Trials tab in the backup section. Rutgeerts P. N Engl J Med. 5;353:-7.

10 ACT 1 and ACT : Clinical Remission ACT 1 and ACT : Mucosal Healing at Week and Week 3 Percent of Patients ACT Weeks 3 Weeks Percent of Patients ACT P<.1 P< Weeks 3 Weeks Proportion of Patients (%) ACT 1 P< Week Week 3 Proportion of Patients (%) P<.1 P<.1 ACT Week Week 3 Placebo infusions 5 mg/kg infliximab 1 mg/kg infliximab Placebo infusions 5 mg/kg infliximab 1 mg/kg infliximab Clinical remission defined as Mayo score of points, with no individual subscore >1. Patients with baseline medication were continued on stable doses. Rutgeerts P. N Engl J Med. 5;353:-7. Mucosal healing defined as endoscopy subscore of or 1. Patients with baseline medication were continued on stable doses. Rutgeerts P. N Engl J Med. 5;353:-7. Summary of ACT 1 and ACT Adverse Events Ileal Pouch Functional Outcome Selected Adverse Events Patients with 1 1 adverse event Headache Upper respiratory tract infections Worsening UC Arthralgia Abdominal pain Infusion reactions Patients with 1 1 serious event Worsening UC Optic neuritis Serious infection Immunogenicity Malignancy Lymphoma Placebo n= 77% 1% 15.% 1.9% 9% 11.9% 9% 19.7% 1.7% % 1.% %.% % Infliximab Combined n= 3.5% 17.% 13% 1.% 1% 1.5% 1.5% 13.%.%.%.3%.5%.% % 1-year postoperative No. of BM/ hours Incontinent (%) Nocturnal seepage (%) Age in Years Majority of patients with UC had other diseases including Crohn s disease, indeterminate colitis, familial polyposis, and cancer. >5. 7 One case each of TB during the study and histoplasmosis (fatal result) during the follow-up extension were reported in patients receiving infliximab. Data on file. Centocor, Inc. Delaney CP et al. Ann Surg. 3;3:1-.

11 Complications of Surgery: Ileal Pouch Anal Anastamosis (IPAA) Mortality (<.5%) 1 3 to 1 stools/ hr 1 Impotence (1.5%) Pouchitis (1%-%) 1 Small bowel obstruction (%) 1 Decrease in female fertility (5%-9%) 3-5 Pouch-vaginal fistula (%) 1 1. Sagar PM, Pemberton JH. In: Satsangi J, et al, eds. Inflammatory Bowel Diseases. Oxford, England: Churchill Livingstone; 3: Pemberton JH et al. Ann. Surg. 197;: Olsen KO et al. Gastroenterology. ;1: Johnson P et al. Dis Colon Rectum. ;7; Gorgun E et al. Surgery. ;13(): Cumulative risk of pouchitis (%) 1 Penna C et al. Gut. 199;3:3. Penna (PSC) N=5 Pouchitis Svaninger (No PSC) N= Penna (No PSC) N=13 7 Years since ileostomy closure Svaninger G et al. Scand J Gastroenterol. 1993;:95. Ileal Pouch: Cumulative Incidences Pregnancy Newer and Improved Therapy of UC Months 1 Controls (n=91) 75% % Before Colectomy (n=) 7% 5% After IPAA (n=19) 1% 7% 5-ASA Oral Prednisone 5-ASA Enema Early use for steroid sparing Patience! Dosing appropriately Monitoring MP/ Azathioprine IV Steroids IV Cyclosporine Surgery P<.1 vs controls. % 9% 3% Maximize dose and delivery system Individualize therapy for effect, adherence Cancer prevention? Infliximab When to use? Olsen KO et al. Gastroenterology. ;1:15-19.