1. Quando sospendere la terapia biologica ? Claudio Bilardi Modulo di Gastroenterologia Ospedale Villa Scassi Genova, 26 Novembre 2011, Hotel Sheraton

2. ECCO Statement 6H (Crohn Disease) No recommendation can be given for the duration of treatment with methotrexate or anti-TNF agents, although prolonged use of these medications may be considered if needed [EL3, RG C]. Potential risks and benefits should be discussed on an individual basis. Dignass A et al, Journal of Crohn's and Colitis, 2010 ECCO statement 6 K (ulcerative Colitis) Due to lack of evidence, no recommendation can be given for the duration of treatment with azathioprine or infliximab, although prolonged use of these medications may be considered if needed [EL4, RG D] Travis S.P.I et al, Journal of Crohn's and Colitis, 2008 ECCO Guidelines

3. IG-IBD Statement 6B (Ulcerative Colitis) One year scheduled treatment with Infliximab can be used in patients who have responded to infliximab induction [EL 1b,RG A]. In patients who are thiopurine-naïve, maintenance therapy with thiopurines alone is a valuable option [EL 5, RG D]. The duration of the therapy over 1 year should be carefully evaluated on a case-by-case basis [EL 4, RG C]. Maintenance therapy with infliximab that achieves only response should be carefully evaluated in the face of a colectomy [EL 5, RG D] A. Orlando and IG-IBD, Digestive and Liver Disease, 2011 IG-IBD Statement 4C (Crohn’s disease) Open experiences have reported long-term effectiveness and safety of anti- TNF_ agents; however, the duration of the therapy over 1 year should be carefully evaluated on a case-by-case basis [EL 4, RG C] Italian Guidelines

4. Key questions to address when starting biologicals 1) What is the aim / endpoint of therapy in my patient? Steroid discontinuation and steroid-free remission? Fistula closure? Bring patient in deep remission? Control of extra-intestinal disease? Mucosal healing, QoL? 2) Are there any contra-indications? e.g. active infection… 3) Do I have to undertake specific actions to maximize response? Do I need to optimize therapy? Should I stop certain therapies? Role of smoking … Treatment goals

5. Induction of remission wk 4:  35-40% (ACCENT I&II, CLASSIC 1); wk 26 (CS-free):  50% (SONIC) Maintenance of remission 1 yr:  35-40% (ACCENT I&II, CHARM, SONIC); 3yr:  30% (ADHERE) Steroid-sparing 1 yr:  25-30% (ACCENT I, CHARM), 40% (GETAID); 3yr:  30% (ADHERE) Mucosal healing (ACCENT I, SONIC, EXTEND, Local cohorts) Reduction of hospitalizations and surgeries (ACCENT I&II, CHARM) Improvement of QoL (ACCENT I&II, CHARM) Anti-TNF alpha in CD Induction/Maintenance of remission and added clinical benefits

6. N=172N=215N=113 Infliximab (ACCENT I) Adalimumab (CHARM) Certolizumab (PRECISE 2) Placebo % pazienti Remissione clinica in terapia con anti-TNF- 

7. Long-term outcome of treatment with IFX in CD Stop of IFX 70/547 patients => side effects (12.8%) Stop of IFX 12/547 patient => other reasons (2.2%) Stop of IFX 118/547 patients => LoR (21.6%) 237/547 CD patients still on IFX with sustained benefit at the end of follow-up (43.3%) 110/547 CD patients stopped IFX due to remission (20.1%); 84 of them (76.4%) still in remission at the end of follow-up 547 CD patients Sustained clinical benefit in 347/547 patients (63.4%) Primary end point Schnitzler F, et al. Gut 2008 Median follow up: 55 months (IQR 27-83)

8. D ’ Haens GR et al, Lancet, 2008 MH at 2 years predicted stable clinical remission MHNo MH % stabje clinical remission

9. Armuzzi A, et al.UEGW 2009 Long-term IFX maintenance therapy Mucosal healing and surgeries in CD MH in 109 CD Median FU: 44 months (IQR 33-63) Median N infusion: 15 (IQR 12-20) Median time on scheduled IFX: 26 months (IQR 20-39) 13 36 56 4 P= 0.001

10. Schnitzler F, et al. IBD 2009 Mucosal healing and long term outcome of Infliximab maintenance therapy (Leuven) Abdominal surgeries Clinical benefit MH No MH MH No MH

11. Baert F, et al. Gastroenterology 2009 Mucosal healing in CD at year 2 predicts sustained clinical remission during year 3 + 4 Percentage of patients (%) 17/24 P=0.036 OR 4.35 (95% CI 1.1-20.8) 6/22 P=0.089 1/24 5/22 New or active draining fistula during Year 3+4 Clinical remission (CDAI<150, no steroids, no resections) during Year 3+4 49 patients from SUTD trial underwent colonoscopy at year 2 FU during year 3 and 4

12. Crohn's disease flares per patient according to mucosal healing status. Baert FJ et al Gastroenterology 2009

13. Early normalization of CRP level and better sustained response Jurgen M et al, Clinical Gastroenterology and Hepatology, 2011

14. CRP level at baseline and at time of first endoscopy and mucosal healing status Jurgen M et al, Clinical Gastroenterology and Hepatology, 2011

15. Armuzzi A, et al. UEGW 2009 Long-term scheduled treatment with IFX in CD Relapse after IFX withdrawal 43 CD 24 (19-34 IQR) months of median IFX scheduled treatment 13 (10-19 IQR) months of median FU since suspension 21 (48.8%) CD relapse MH and low CRP at discontinuation positive predictors of sustained remission after IFX withdrawal. MH No MH Low CRP High CRP

16. Maintenance of clinical benefit in Crohn’s disease patients after discontinuation of infliximab Waugh A.W G et al, Aliment Pharm Ther, 2010 Between July 2000 and July 2007, 354 patients with Crohn’s disease completed a three-dose induction regime with infliximab and entered into maintenance infliximab dosing every 8 weeks Of those patients who entered into maintenance infliximab treatment, a total of 48 patients were eligible to be included in the cohort for this study if they had responded to infliximab, maintained a stable corticosteroid-free clinical benefit for at least 6 months and discontinued the infliximab for reasons other than loss of response.

17. Maintenance of clinical benefit in Crohn’s disease patients after discontinuation of infliximab Waugh A.W G et al, Aliment Pharm Ther, 2010

18. At the time of infliximab discontinuance, 44% of the patients were receiving azathioprine, 19% methotrexate and 4% mercaptopurine as concomitant immunosuppressive therapy. Maintenance of clinical benefit in Crohn’s disease patients after discontinuation of infliximab Waugh A.W G et al, Aliment Pharm Ther, 2010 Kaplan–Meier analysis of the proportion of patients with sustained clinical benefit demonstrated that 50% relapsed within 477 days after infliximab discontinuance. In contrast, 35% of patients remained well, and without clinical relapse, up to the end of the nearly 7-year follow-up.

19. STORI trial (GETAID) IFX discontinuation in CD patients in stable remission Louis E, et al DDW 2009 Aims & Methods: -To assess the risk and identify factors of CD relapse in a prospective cohort study of 115 patients with luminal CD -Patients received last IFX infusion at baseline and were followed up at week 2 and every 2 months. IS was kept at a stable dosage -Discontinuation of IFX after IFX + IS > 1 yr and have a stable remission wihtout steroids for > 6 months -Median FU: 12 months -Demographic, clinical and biological factors were evaluated for their potential association with the time-to-relapse through log-rank method and hazard ratio (HR) was estimated through Cox model

20. Predictive factor of relapse (multivariate)HRHR P Hb ≤14.5 g/dl/ > 14.5 g/dl4.68 (1.4-15.3)0.0016 IFX through levels ≥ 2/ <2 mg/ml2.94 (1.3-6.7)0.0058 CRP ≥ 5 / < 5 mg/L3.79(1.9-7.4)0.0002 CDEIS ≥ 2 / < 23.05 (1.6-5.7)0.0007 Louis E, et al DDW 2009 STORI trial (GETAID) IFX discontinuation in CD patients in stable remission

21. Louis E, et al DDW 2009 Results: 52 relapses recorded 5 withdrawal before re-treatment (patient (n=4) or investigator decision 47 re-treatments 37 evaluated responsed to re-treatments at 4 weeks 36/37 remissions with no complications

22. Endoscopic (CDEIS) and biological markers (including hemoglobin, US CRP, IFX trough levels) of inflammation permitted the identification of patients with very low or very high risk of relapse Endoscopic and biological markers of activity are low in patients with stable clinical remission under combined IFX + IS therapy More than half of the patients have not relapsed one year after IFX discontinuation In relapsing patients, re-treatment with IFX was successful and well tolerated in almost all patients Louis E, et al DDW 2009 STORI trial (GETAID) IFX discontinuation in CD patients in stable remission Conclusions:

23. Conclusioni Le linee guida (sia italiane che internazionali) non indicano quale debba essere la durata del trattamento Pochi studi hanno analizzato questo aspetto mettendo in evidenza il concetto di remissione profonda ed identificando alcuni markers del probabile mantenimento della risposta. E’ necessario sviluppare altri fattori predittivi che ci aiutino ad individuare il paziente candidato alla sospensione della terapia