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

Transcription

1 Crohn's Disease The What, When, and Why of Treatment Sunanda Kane, MD, FACG Professor of Medicine Department of Gastroenterology and Hepatology Mayo Clinic Rochester, MN In my lecture today, I will be discussing off label use of several medications to treat Crohn s disease 1

2 Nancy 30 year old female presents with 3 month history of perianal pain and drainage without change in stool habits Treated empirically with metronidazole with only minimal improvement Colonoscopy with TI intubation and biopsy show evidence of patchy colitis with rectal involvement c/w Crohn s disease FH: positive for Crohn s in brother PE: Normal except rectal exam which showed 3 Nancy 4 2

3 Cumulative Incidence of Crohn s Fistulas Schwartz DA, et al. Gastroenterology. 2002;122(4): Frequency of Perianal Fistulas According to Anatomic Location of Bowel Involvement Colon only (without rectal involvement) 41% Small intestine only 12% Rectum only 92% Combined ileocolic involvement 15% Hellers G, et al. Gut. 1980;21(6):

4 Park s Classification of Perianal Fistulas Extrasphincteric External anal sphincter Trans sphincteric Superficial Parks AG. Br Med J. 1961;1(5224): Intersphincteric Suprasphincteric 7 Simple vs Complex Fistula Simple Complex Sandborn WJ, et al..gastroenterology. 2003;125(5):

5 Diagnostic Options Used in the Classification of Perianal CD History Physical Exam Imaging Fistulography CT MRI Endorectal ultrasound 9 What Happens When Fistulas are Missed at Time of EUA? N=71 52% of patients needed repeat surgery in cases where surgery and MRI disagreed Fistula recurrence was always at site predicted by MRI Buchanan G, et al. Lancet. 2002;360(9346):

6 Does Controlling Fistula Healing Make a Difference? N = 32 Percent of Patients 100% 80% 60% 20% 0% Fistula Recurrence 79% 44% Inflix Only EUA Before Inflix 120% 100% 80% 60% 20% 0% Response to Treatment 100% 83% Inflix Only EUA Before Inflix p=0.014 p=0.001 Requeiro M, et al. Inflamm Bowel Dis. 2003;9(2): Setons Prevent Abscesses by Preventing Premature Closure of Fistula Tract Rosen, MJ. Clin Gastroenterol Hepatol. 2010;8(1):

7 Medical Therapies Antibiotics (metronidazole, ciprofloxacin) Antimetabolites Azathioprine 6 mercaptopurine Methotrexate Cyclosporine Tacrolimus Biologic Agents Infliximab Adalimumab Certolizumab 13 Antibiotics Metronidazole: typical dose is mg po tid/qid, improvement seen after 6 8 weeks Most studies are open label Largest study conducted by Bernstein et al 1 21 patients studied, healing seen in 83% Three other studies found healing rate of 34 50% 2 5 Fistulas re occur once medicine is stopped Adverse events include metallic taste, glossitis, nausea and a distal peripheral sensory neuropathy 1. Bernstein LH, et al. Gastroenterology. 1980;79(2): Schneider MU, et al. Dtsch Med Wochenschr. 1981;106(36): Jakobovits J, et al. Am J Gastroenterol. 1984;79(7): Schneider MU, et al. Dtsch Med Wochenschr. 1985;110(45): Brandt LJ, et al. Gastroenterology. 1982;83(2):

8 Antibiotics Fistula Response Percent Fistula Response at 10 weeks p= % 13% 10 0 N=10 N=7 N=8 Cipro Metronidazole Placebo Thia KT, et al. Inflamm Bowel Dis. 2009;15(1): Azathioprine / 6MP Five controlled trials were summarized in a metaanalysis 1 22 / 41 (54%) of patients who received AZA /6 MP responded vs. 6 / 29 (21%) who received placebo Pooled odds ratio was 4.44 in favor of fistula healing No dedicated trials post hoc subgroups Pearson DC, et al. Ann Intern Med. 1995;123(2):

9 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): 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

10 Minimizing Toxicity from Thiopurines Check TPMT first to rule out those with low enzyme activity Schedule regular CBC, liver enzymes Educate patient on symptoms to watch for Dosing at night anecdotally alleviates some complaints of nausea Vaccinate patients for age appropriate diseases prior to initiation Kane S. Curr Gastroenterol Rep. 2010;12(6): Tacrolimus (FK-506) 50% 30% 20% 10% 0% p= % 8% Tacrolimus Placebo Improved Double blinded study n=48 Randomized to receive 0.20 mg/kg/day for 10 weeks Primary endpoint: improvement defined as closure of > 50% fistulas and maintenance of closure for >4 weeks Only 10% had closure of all fistulas Sandborn WJ, et al. Gastroenterology. 2003;125(2):

11 Infliximab for Crohn s Perianal Fistulas 80% 60% 20% 0% 68% 56% 26% Placebo 5 mg/kg 10mg/kg P<0.001 P=0.041 Initial fistula response to infliximab n=94 Primary endpoint: > 50% reduction in open fistulas Present DH, et al. N Engl J Med. 1999;340(18): Accent II: Infliximab for Maintaining Fistula Closure Percent Placebo 36 5 mg/kg Percent of patients maintaining complete fistula closure n= weeks Primary endpoint: > 50% reduction in open fistulas p= Sands BE, et al. N Engl J Med. 2004;350(9):

12 Adalimumab: Complete Healing of Draining Fistulas 60% 50% 30% 20% 10% 0% 48% 39% 29% 14% Placebo 40 mg eow 40 mg weekly Both groups Weeks 26 and 56: Randomized responders in CHARM trial n=70 Colombel JF, et al. Gastroenterology. 2007;132: Proportion of Fistula Responders with Fistula Closure Percent 80% 70% 60% 50% 30% 30.8% 67.7% Week 26 on Certolizumab Pegol PRECiSE 2 subgroup 20% 10% 0% Placebo Certolizumab Schreiber S, et al. Aliment Pharmacol Ther. 2011;33(2):

13 Proportion of Fistula Responders with Fistula Closure 35% 30% 25% 20% 15% 10% 5% 0% p= % 36% Placebo CZP 400 mg Q4w N=13 N=15 Week 26 on Certolizumab Pegol PRECiSE 2 subgroup Schreiber, et al. Presented at: Crohn's and Colitis Foundation of America 2008 Advances in Inflammatory Bowel Diseases; Hollywood, Florida; December 4-7, Abstract O Schreiber S, et al. Aliment Pharmacol Ther. 2011;33(2): 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):

14 Minimizing Toxicity for Anti-TNF Therapy Rule out evidence for TB prior to initiation If immunocompromised, PPD and Quantiferon may be negative Rule out active infection prior to initiation Abscess C difficile CMV Vaccination for age appropriate diseases Kane S. Curr Gastroenterol Rep. 2010;12(6): Minimizing Toxicity for Anti-TNF Therapy Check serologies for Hepatitis B Assess for signs/symptoms of: Uncontrolled heart failure Demyelinating disorders (MS) Skin cancers/suspicious moles Kane S. Curr Gastroenterol Rep. 2010;12(6):

15 Approach to the Crohn s Disease Patient with a Perianal Fistula 1. History and physical exam 2. Endoscopy to assess activity of Crohn s disease 3. Imaging study (EUS or MRI) to delineate perianal disease process 4. Exam under anesthesia (EUA) Simple Fistula Without Rectal Inflammation Simple Fistula With Rectal Inflammation Complex Fistula Antibiotics and AZA/6 MP Consider anti TNF Antibiotics, AZA/6MP and Anti TNF (Consider monitoring healing with repeat imaging study) 1. Seton placement 2. Antibiotics, AZA/6 MP and Anti TNF (Consider monitoring healing with repeat imaging study) Treatment Failure Treatment Success Treatment Failure Treatment Success Treatment Failure Treatment Success 1. Fistulotomy 2. Consider fibrin glue, fistula plug or endorectal advancement flap 3. If 1 or 2 fails, treat as complex fistulizing process Continue maintenance AZA/6 MP and Anti TNF (if started) Treat as complex fistulizing process Continue maintenance AZA/6 MP & Anti TNF Consider Tacrolimus in selected pts Proctectomy 1. Remove seton 2. Continue maintenance AZA/6 MP and Anti TNF 29 Nancy: Follow-Up Patient underwent rectal EUS which confirmed trans sphincteric fistula with associated abscess (complex fistula) Received appropriate vaccinations Underwent EUA with seton placement and started azathioprine, 2.5 mg/kg/day (TPMT nl) and an anti TNF Setons removed 4 months later once rectal EUS demonstrated an inactive fistula Continued maintenance azathioprine and anti TNF 30 15