Medical Management of Small bowel Crohn s Disease: An evidence-based approach

Transcription

1 Medical Management of Small bowel Crohn s Disease: An evidence-based approach E. Jan Irvine, M.D., F.R.C.P.(C)., M.Sc. Professor of Medicine, University of Toronto, Head, Division of Gastroenterology, St. Michael s Hospital, Toronto Ontario, Canada

2 Learning objectives After this presentation participants will be able to: Understand the goals of therapy for Crohn s disease Identify the most effective evidence-based therapies for active small bowel Crohn s disease and maintenance of remission

3 Goals of Therapy Induce and maintain remission Steroid sparing Heal mucosa Minimize disease and treatment toxicity Optimize quality of life (Select optimal timing for surgery)

4 General Considerations Crohn s disease diagnosis (history, physical exam, stools, serology) Extent, location, behavior (inflammatory, stricturing, penetrating) Imaging- endoscopic, radiologic Disease severity Stool frequency, rectal bleeding, pain, weight loss, extraintestinal, Blood work: CBC, CRP, albumin, B12. Response to therapy Drug, dosage, duration

5 Targets for Anti-inflammatory Therapy Luminal bacteria (antibiotics, probiotics) T-cell activation (immunomodulators) Cytokine modulation Signal transduction T-cell and helper subsets Adhesion molecules and leukocyte recruitment Non-specific mediators of injury and repair

6 Mild/Moderate and Moderate/Severe* Ambulatory Eating without: Dehydration Toxicity Abdominal tenderness Pain or mass Obstruction >10% weight loss Stool frequency, bleeding Assess well-being, social function. Not responding to Rx Or with more prominent Fever Weight loss Abdominal pain/tenderness Nausea/vomiting (nonobstructve) Anemia *Symptoms on steroids with Obstruction Rebound Cachexia abscess Hanauer SB, Sandborn W. Am J Gastroenterol 2001;96:637

7 Crohn s disease-step-up therapy Active CIR Budesonide Prednisone 6-mercaptopurine or azathioprine (methotrexate) Infliximab Remission 5-ASA? Post operative prevention only 13% benefit CIR budesonide 6Mercaptopurine/Azathioprine or methotrexate Infliximab

8 Sulfasalazine in active CD Modest benefit at best Active colonic, ileocolonic 1g/15kg up to 5g/d given for at least 12 weeks National Cooperative Crohn s Study - 17wks) Placebo 30% remission p<.05 SASP 43% remission Benefit 13% NNT=8 Primary effect in colonic disease; predictors of no benefit: prior steroid use and small bowel involvement Summers RW et al. Gastroenterol 1979:77:847-69

9 Pentasa in active Crohn s disease: Meta-analysis 5-ASA in doses < 3g/d are not effective for active Crohn s disease Akobeng AK, Garderer E. Cochrane Database Syst Rev Jan 25;(1):CD Pentasa 4g/day and placebo (619 pts) Ileocecal pts had decrease of 63 points in CDAI for Pentasa vs. 45 for placebo (delta of 18) Is this a clinically important benefit? Hanauer S:B et al. Clin Gastroenterol Hepatol 2004;2:379-88

10 Toxicity Sulphasalazine (10-45%) Headache, nausea, epigastric pain, diarrhea, (reduced sperm count & motility) Idiosyncratic (3%) Stevens-Johnson syndrome, pancreatitis, agranulocytosis, or alveolitis Mesalamine (15%) Diarrhoea (3%), headache (2%), nausea (2%), and rash (1%) are reported Renal disease (interstitial nephritis), pancreatitis significantly more common with mesalamine Carter MJ et al. Gut 2004; 53:v1-v16

11 Budesonide vs. Placebo in Active CD P < NNT = 4 % Remissio placebo budesonide 10 0 Greenberg 1994 Tremaine 2002 Greenberg GR et al New Engl J Med 1994;331:836 Tremaine WJ et al. Amer J Gastroenterol 2002;97:1748

12 Budesonide in active CD Superior to placebo (2 studies): ABI 23% NNT = 4 Superior to 5-ASA (1 study): ABI 26% NNT = 4 Conventional CS superior (5 studies) Similar benefit low activity group (data not given for high activity group) Adverse events reduced in budesonide ARR 21% NNT = 5 (heterogeneity present; serious ADE not separated) Kane, S. V et al. Alimentary Pharmacology & Therapeutics, 2002; 16:1509 Recent randomized trial lesser bone loss at 2yrs budesonide vs. prednisolone (1% vs. 3.8%) steroid naïve patients only Schoon EJ et al. Clin Gastroenterol Hepatol 2005;3:

13 Corticosteroids in active CD Suppresses IL transcription, arachidonic acid metabolism, induces stability NFΚB complex, and apoptosis of lymphocytes (lamina propria). Author Duration (wks) Dose (mg pred/kg/d) N Rem n Placebo CS OR NNT Summers Malchow Modigliani

14 Corticosteroid toxicity Early supraphysiological doses» cosmetic (acne, moon face, oedema)» sleep and mood disturbance» dyspepsia» glucose intolerance. Prolonged (>12 weeks)» posterior subcapsular cataracts, osteoporosis, osteonecrosis femoral head, myopathy, and susceptibility to infection. Long-term withdrawal» adrenal insufficiency» myalgia, malaise, and arthralgia» raised intracranial pressure. Carter MJ et al. Gut 2004; 53:v1-v16

15 Azathioprine and 6MP in acute CD 9 trials OR Active 3.09 (95% CI, 2.45 to 3.91) After 17 wks OR increased NNT = 3-6 Steroid sparing effect: NNT = 3 Pearson DC et al. Ann Int Med 1995;122:132 Sandborn WJ et al. Cochrane Database Syst Rev. 2000;(2):CD

16 Methotrexate: Evidence from single RCT MTX 25 mg i.m. weekly Limited efficacy active disease; Meta-analysis: Significant heterogeneity of 5 published trials 50 Remission % 25 P = Placebo Methotrexate 25 mg/wk 0 All patients >20mg/d <20 mg/d Treatment group Feagan BG et al. New ENgl J Med 1995;332:292 Alfadhli AA et al. Cochrane Database Syst Rev Jan 25;(1):CD003459

17 Infliximab: the CA2 Trial: Clinical response and remission in patients with active Crohn s disease P< Response (%) % 64% 4% P= % Placebo N = 25 Infliximab 5, 10 and 20mg/kg N= week clinical response 4 week clinical remission Targan SR et al. New Eng J Med 1997;337:1029

18 Drug Toxicity Toxicity of Infliximab Lymphoma, infusion reactions, delayed hypersensitivity, severe infections (TB assessment CXR, TB skin test) Methotrexate CBC, LFT s monthly, liver biopsy if high risk, pneumonitis, hepatotoxicity AZA/6MP CBC, LFT s monthly, metabolites-if available, for hepatotoxicity Pancreatitis, rash, opportunistic infection, lymphoma

19 Evidence-based algorithm for small bowel CD Pentasa (?clinical significance of benefit) Budesonide (ileocecal CD) mild/moderate Conventional corticosteroids administered for 8 16 wk more severe Relapse 6 12 months another cycle of induction therapy; maintenance azathioprine, 6- mercaptopurine, or methotrexate) budesonide 6mg od. alternative to immunosuppressive or for prednisone-dependent patients. Sandborn WJ. Am J Gastroenterol (12 Suppl):S1-5. Hanauer SB, Stromberg U. Clin Gastroenterol Hepatol. 2004;2: Sandborn, WJ, Feagan BG Aliment Pharmacol Ther. 2003;18:263-77

20 Number needed to treat active small bowel CD Active Infliximab 3 Corticosteroids 2/3 Budesonide 4 (ileocecal) Azathioprine 7 (steroid sparing) 3 Methotrexate 5 (steroid dep t)

21 Crohn s Remission Maintenance 5-ASA marginal benefit (13%) in post-operative but not medically treated patients Camma C et al. Gastroenterol 1997;113:1465 Corticosteroids Not conventional (high ADE) Budesonide 6mg/d for steroid dependent pts Mantzaris et al Clin Gastro Hepatol2003;1:122; Cortot A ET al. Gut MP/AZA Benchmark Rx Relapse 21% 18mons vs. 8% continued if remission for 42 mons pre-randomization Lemann M et al;. Gastroenterol 2002

22 Crohn s Remission Maintenance Metronidazole 20mg/kg/d for 3 mons Significant at 3 mons but not 1-3yrs, high ADE Rutgeerts P et al, Gatroenterol Methotrexate 15 mg s.c. weekly for 40 wks 65% vs. 39% placebo. Infliximab Feagan B et al. NEJM 2000 ca2 Trial Rutgeerts et al ACCENT I Plac. 21%, 5mg 39%, 10mg 45% (every 8 weeks) Shorten interval, increase dose to improve efficacy. Hanauer SB et allancet 2002

23 Azathioprine and 6MP in remission CD 5 trials of 319 patients: one yr. remission 67% for AZA vs. 52% for placebo OR Quiescent disease 2.27 (CI, 1.76 to 2.93) NNT = 7 Pearson DC et al. Ann Int Med 1995;122:132 Sandborn WJ et al. Cochrane Database Syst Rev. 2000;(2):CD

24 Methotrexate for remission maintenance N = 76; 15mg; i.m. weekly % P = placebo methotrexate 0 remission Feagan B et al. New Engl J Med 2000;342: 1627

25 Maintenance IFX Therapy: ACCENT I Trial Multicenter RDBPCT (45 centers in NA, Europe, Israel; N = 573; CDAI >220, all given IFX 5mg/kg, responders randomized 3 groups for 46wk Infliximab 5mg/kg Responders only 335 pts (58%)responded Placebo wks 2, 6 and Q8wks, N=110 Infliximab 5mg/kg wks 2,6,Q8wks, N=113 Infliximab 5mg/kg wks 2,6; 10mg/kg Q8wks, N=112 Group I Group II Group III Hanauer SB et al. Lancet 2002;359:1541

26 Results week 54 Accent I 60 P =.002 P < % P = P=.244 Group I Group II Group III 10 P =.003 P= Remission Response Hanauer SB et al. Lancet 2002;359:1541

27 Infliximab - Infusion Reactions Acute: adverse reaction during or within 24 hrs of initial or subsequent infusions Delayed: adverse reaction from 24 hrs to 14 days after re-treatment Loss of responsiveness Symptoms: Arthralgia Myalgia Urticarial rash Fever Malaise Management: Acetominophen Antihistamines Steroids (200 mg i.v.)

28 Infliximab Guidelines (CAG) Induction: wk 0 5mg/kg (or 3 dose induction 0/2/6 augments response 15%) If inadequate response 2 nd dose 2weeks If inadequate response (consider 10mg/kg) Repeat dosing Q8weeks 5mg/kg Recommended concomitant immunosuppressives Guidelines for prevention of infusion reaction Panaccione R et al. Can J Gastroenterol 2004;18:503

29 Extensive small bowel disease No RCT specific data Systemic cortcosteroids Early immunomodulation (azathioprine or 6MP[methotrexate]) Steroid dependent or refractory proceed to immunomodulators Infliximab ECCO Consensus Travis SP et al. Gut 2006;55Suppl1:i16-35

30 Fistulizing Crohn s Disease IFX for fistulae-94 pts with abdominal or perianal fistulae RCT 68% 5mg/kg vs. 56% 10,g/kg vs. 26% placebo P<.02 50% decrease number of draining fistulae Present D et al. New Engl J Med. 1999;340:1398 ACCENT II IFX for maintenance of fistulizing disease 195/306 (0/2/6) responders at week 10/14 randomized Time to loss of response 40wks (IFX5mg/kg 8weekly) vs. 14 weeks (placebo) P<.001) Wk 54 36% IFX complete closure vs. 19% placebo P =.009 Sands B et al. New Engl J Med 2004;350:876 Tacrolimus for fistulae 10 week RCT.2mg/kg/d 43% decrease 50% vs. 8% (p=.004) 10% vs. 8% for remission (p=.86) Sandborn WJ et al. Gastroenterol 2003;125:380

31 Stricturing small bowel Crohn s disease Anecdotal evidence dilatation of short strictures (<4cm) Accessible by endoscopy using TTS balloon dilatation Multiple sessions Risks: bleeding, perforation (1% to 4%) Multiple, proximal resection, stricuturoplasty Risks: short bowel Low fiber diet, intermittent antibiotics

32 The ideal management of CD: Top down vs. step-up? Top Down = IFX 5mg/kg 0-2-6/AZA 2.5mg/kg (rescue:ifx &/or MTX) Step Up = pred 40/8wk taper (rescue repeat CS then AZA then IFX) P=.006 P < % Top down Step-up Success Steroids MTX/AZA/6MP Hommes D et al. DDW 2005/Gastroenterol in press

33 Summary: medical therapy for small bowel CD Acute and chronic Budesonide 9mg/d mild/mod ileocecal disease 6mg for maintenance in some patients Prednisone 40-60mg/d mod/severe; i.v. steroids No role in maintenance Add AZA/6MP or methotrexate for early relapse or steroid dependence Use infliximab if steroid resistant, only partial response for induction, or fistulizing Reserve infliximab maintenance for AZA/6MP/MTX allergic or unresponsive Surgery

34 Promising therapies not yet approved or in trials Trichuris suis-phase III?Natalizumab (SAM) PML toxicity 3 deaths MLN-02, LDP-02 Adalimumab CDP870 MRA Sargramostim (GMCSF) Filgrastim Probiotics (VSL-3) Stem-cell transplantation Leukophoresis Antibiotics Somatropin (human growth hormone) CNI-1493 (MAP-K inhibitors)

35 Acute therapy of Crohn s Disease Amino-salicylates Induction of remission mild only Prevention post-operative Antibiotics or budesonide Induction of remission in CD Corticosteroids Induction moderate and severe Crohn s disease Ineffective maintenance Immunomodulators Induction moderate and severe Effective maintenance Biologicals Induction and maintenance Perianal Other

36 Crohn s disease monitoring (endpoints for RCT) CDAI (Crohn s disease activity index) (<150) #stools, abdominal pain, well being, need for antidiarrheal, abdominal mass, Hct, body weight, extra-gi symptoms Best WR et al Gastroenterol 1976; 70:439; Gastroenterol 1979;77:843. CDEIS (Crohn s disease endoscopic index severity) Stenosis, deep ulceration, superficial ulceration and % affected Mary JY, Modigliani R. Gut 1989;30:983; D Haens G et al. Histological Severity Damage (epithelium, architecture), inflammation (l.p.-mono/pmn; epithelium-pmn), eriosion/ulcer; granuloma; % affected. Geboes K et al. Gut 2000;7:404 Perianal Disease Activity Pain, discharge, restricted sex, induration, worst finding. Irvine EJ. J Clin Gastroentetrol 1995;20:27 Laboratory parameters C-reactive protein (ESR); fecal calprotectin; other. Vermeire S et al. Inflamm Bowel Dis ;10: Roseth A et al. Digestion 197;58:176 HRQOL Generic (e.g. SF-36, PQWB), Disease specific (IBDQ) Ware, J. Med Care 1992;30:473 Guyatt G et al, Gastroenterol 1989;96:804

37 Treatments that are not recommended or are in effective in active small bowel CD 5-ASA <3g/d for acute CD; or for remission maintenance Antibiotics Cyclosporine IL-10 Alicaforsen (anti-icam1) Etanercept, onercept

38 Chronic active (steroid refractory, dependent) Steroid-refractory: active disease despite adequate dose and duration of prednisolone (> 20 mg/d for 2 weeks). Steroid dependent: relapse when steroid reduced below 20 mg/day, or within 6 weeks of stopping or requiring >10mg for 4/12 previous months.

39 6-MP Metabolism 6-TU 6-TG nucleotides DNA RNA AZA XO 6-MP HPRT 6-TIMP TPMT 6-MMP Circulation TPMT 6-MMP ribonucleotides Intracellular Purine synthesis

40 Grading Evidence and Recommendations Ia - From meta-analysis of RCTs Ib - From >1 RCT IIa - Well-designed, controlled non-randomized study IIb Well-designed experimental study design IIIa Non-experimental design IV - Expert opinion, descriptive, anecdotal evidence A = Recommendation based on Evidence Ia or Ib B = Recommendation based on Evidence IIa, IIb or III C = Recommendation based on Evidence IV

41 Step-up vs. step-down treatment (small bowel) Infliximab Azathioprine Corticosteroids Budesonide 5-Aminosalicylates or no treatment