Ali Keshavarzian MD Rush University Medical Center

Transcription

1 Treatment: Step Up or Top Down? Ali Keshavarzian MD Rush University Medical Center

2 Questions What medication should IBD be treated with? Can we predict which patients with IBD are high risk? Is starting early biologic therapy beneficial for some patients? ts How can we avoid over treating patients?

3 Questions What medication should IBD be treated with? Can we predict which patients with IBD are high risk? Is starting early biologic therapy beneficial for some patients? ts How can we avoid over treating patients?

4 Step Up Approach Severe Surgery anti-tnf-α Moderate MTX AZA / 6-MP Systemic steroids AZA = Azathioprine 6-MP = 6- Mercaptopurine MTX = Methotrexate Mild Budesonide Antibiotics 5-ASA 5-ASA= 5-aminosalicylic acid Adapted from: Hanauer et al, Am J Gastroenterol 2001; 96: 635

5 Mucosal Healing in Crohn s Therapy Mucosal Decreased Decreased Healing Need for Recurrence Surgery after Surgery Corticosteroids No No No Imuran or 6-MP Yes No Yes Methotrexate Yes No Unknown Anti-TNF Yes Yes Yes Enteral Nutrition Yes No Unknown G Van Assche et al., Nature Reviews in Gastro, 2010

6 Construct of Anti-TNF TNF-α Biologic Agents Infliximab Adalimumab Certolizumab Pegol VL VH No Fc CH 1 PEG IgG 1 IgG 1 PEG Chimeric monoclonal antibody (75% human IgG 1 isotype) Human recombinant antibody (100% human IgG 1 isotype) Humanized Fab fragment (95% human IgG 1 isotype) Mouse Human PEG, polyethylene glycol.

7 Biologic era in IBD management: Healing of refractory ulceration/fistula with Infliximab Pretreatment 4 Weeks posttreatment Pretreatment 2 Weeks 10 Weeks 18 weeks van Dullemen HM et al. Gastroenterology. 1995;109:129. Present DH, et al. N Engl J Med. 1999;340:

8 Top Down Approach Step-up p approach Biologics (TNF Antagonists) Immunosuppressives Corticosteroids Top-down approach 5-Aminosalicylates and Antibiotics D Haens GR, et al. Lancet :

9 Questions What medication should IBD be treated with? Can we predict which patients with IBD are high risk? Is starting early biologic therapy beneficial for some patients? ts How can we avoid over treating patients?

10 Case #1 54 yo M presents with BRBPR for 8 weeks associated with urgency 4-5 BM/day No weight loss He has no prior treatment Quit smoking 1 year ago

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12 UC: Natural History Disease Severity at Presentation Patients with UC (% %) Severe Activity (9%) Moderate Activity (71%) Mild Activity (20%) Mild Activity: < 4 stools daily No systemic disturbance ESR: Nl Moderate Activity: > 4 stools daily Minimal systemic effects Severe Activity: > 6 stools daily Bloody stools Fever Tachycardia Anemia ESR > 30 mm/hr Disease Activity Hendriksen C, Kreiner S, Binder V. Gut 1985;26:

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15 Comparative Doses: Mild to Moderate UC Recommended Treatment Dose Equivalent 5-ASA dose Sulfasalazine 3-4 grams grams Mesalamine 2.4 grams 2.4 grams Balsalazide l grams grams

16 Oral (2.4 g) vs. Rectal (4 g) Mesalamine for Distal UC % Resp ponse Oral 50 Rectal week 2 weeks 3 weeks 6 weeks Combined Safdi. Am J Gastroenterol 1997

17 Case #2 19 year old male presents with 24 weeks of diarrhea, 6-8 BM/day occasionally bloody LLQ abdominal pain weight loss of ~20 lbs Has perirectal fistula on exam Current smoker On oral prednisone at 40 mg the last month without improvement

18 Colonoscopy

19 Disease Course CD Natural History 10% continual active disease 50% intermittent flare at least every 5 yrs 90% flare at least every 10 years Risk of surgery 60% at 10 yrs, 80% at 20 yrs Heterogeneous Around 40% of patients never need steroids

20 Development of stricturing and fistulizing CD over the course of the disease Cumulativ ve Probabil lity (%) Penetrating Inflammatory Stricturing Months Patients at risk: N = Cosnes J et al. Inflamm Bowel Dis. 2002;8:244

21 Response to Steroids at 1 year Faubian et al. Gastroenterology 2001; 121: 255.

22 Clinical Response and Remission P< with Infliximab 81% % Patients P< Placebo (n=25) 48% REMICADE 5 mg/kg 40 (n=27) 20 16% 4% 0 4-week Clinical 4-week Clinical Response Remission i Targan SR, et al. N Engl J Med. 1997;337:

23 Top Down Approach Step-up p approach Biologics (TNF Antagonists) Immunosuppressives Corticosteroids Top-down approach 5-Aminosalicylates and Antibiotics D Haens GR, et al. Lancet :

24 How do we determine which patients have severe disease and may benefit despite risks?

25 Variable Predictors of Disabling Disease: Requirement for Steroids Is Turning Point 5-year clinical course after diagnosis Nondisabling, % Disabling, % (n = 166) (n = 957) P value Age at onset < 40 years years Location of disease Small bowel only Small bowel + colon Colon only Smoking status Smoker Ex or nonsmoker Perianal lesions at diagnosis Yes No Required steroids for first flare Yes No Beaugerie L et al. Gastroenterology. 2006;130:

26 Predictors Disabling Crohn s Independent Predictors 5 years after diagnosis Initial requirement for steroid use, OR 3.1 [ ] Age < 40, OR 2.1 [ ] Perianal Disease, OR 1.8 [ ] PPV for multiple factors 2 factors PPV 91% 3 factors PPV 93% Beaugerie L. et al. Gastroenterology 2006

27 Mucosal Healing in Crohn s Therapy Mucosal Decreased Decreased Healing Need for Recurrence Surgery after Surgery Corticosteroids No No No Imuran or 6-MP Yes No Yes Methotrexate Yes No Unknown Anti-TNF Yes Yes Yes Enteral Nutrition Yes No Unknown G Van Assche et al., Nature Reviews in Gastro, 2010

28 Mucosal Healing at Year 2 Predicts Remission i in Year 3 and 4 SES 0 SES 1-9 % of Pa atients in Rem ission p= p= Remission off Steroids Off Steroids and no TNF Baert F et. al, Gastroenterology, 2010

29 Infliximab: ACCENT I Endoscopic Healing and Reduced Hospitalizations and Surgeries: Infliximab maintenance for Crohn s disease 50 46% Patients with no healing Rate of Ho ospitalizat tions and Sur rgeries (% %) % 8% Patients with healing at 1 visit (10 or 54 wk) Patients with healing at both 10 and 54 wks 0 (34*) (4*) (6*) 0% Hospitalization 0% Surgery 0% *Number per 100 patients Rutgeerts P et al. Gastroeintestinal Endoscopy

30 Conclusions There is no one size fits all to IBD therapy Early therapy to biologic therapy is associated with better clinical outcomes however these drugs have rare but potentially serious side effects Top Down therapy exposes too many patients Top Down therapy exposes too many patients to the risk of these medications

31 Conclusions Careful patient selection is needed Better predictive and surrogate markers are needed to determine where benefit will outweigh risk for biologic therapy Endoscopic mucosal healing is currently one of doscop c ucosa ea g s cu e t y o e o the best surrogate marker of disease modification