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Onali S. IBD: Cosa è cambiato nella Terapia. ASMaD 2013
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Onali S. IBD: Cosa è cambiato nella Terapia. ASMaD 2013

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  • Ad oggi non esiste una definizione univoca e validata di mucosal healing o meglio ancora di endoscopic healing. <br /> La definizione operativa maggiormente utilizzata nei trial clinici per la malattia di Crohn è la completa assenza di lesioni ulcerose (ACCENT I, SONIC, STORI, EXTEND, STEP-UP/TOP-DOWN, MUSIC). <br /> Sono stati tuttavia presentati dati anche sul miglioramento complessivo degli score endoscopici (STORI, MUSIC, EXTEND) con cut-off proposti ma non validati a 3 punti (ma anche in alcune analisi &lt;7) per CDEIS e 5 punti per SES-CD. <br /> Per la colite ulcerosa si utilizza generalmente la definizione basata sulla scomparsa delle lesioni mucosali, oltre alla risposta clinica, e nei trial clinici è spesso utilizzata la definizione operativa della riduzione del Mayo score a: <br /> 0 = normalità <br /> 1 = lieve attività residua, ossia al più granulosità della mucosa e perdita del reticolo vascolare, senza erosioni, fragilità da contatto o ulcere. <br />
  • Negli anni ’90 gli studi del GETAID avevano dimostrato: <br /> l’assenza di significative correlazioni tra l’attività clinica di malattia (misurata con lo score CDAI) e l’attività endoscopica a seguito dei trattamenti con steroidi <br /> la non predittività del miglioramento endoscopico sulla prognosi a lungo termine, oltre all’inutilità dell’intensificazione del regime steroideo per ottenere un miglioramento endoscopico ulteriore. <br /> Per la prima volta con l’uso dell’infliximab vengono dimostrate correlazioni significative tra le variazioni favorevoli dello score CDAI (in ordinata nel grafico) e dello score endoscopico CDEIS (in ascissa nel grafico). <br /> Tale correlazione, significativa per i trattati con IFX (r=0.561 con p=0.002) che nel grafico sono rappresentati dai pallini pieni, è assente per i trattati con placebo che nel grafico sono rappresentati dai triangoli (in arancione nel grafico). <br /> Queste osservazioni derivano da un sottogruppo di pazienti trattati nello studio iniziale pubblicato da Targan e colleghi e vengono riportate in un lavoro di D’Haens e colleghi nel 1999. Vi sono poi le osservazioni relative allo studio di follow-up del Step-up Top-down trial. <br /> La premessa è che il 73% dei pazienti sottoposti alla strategia Top-down e solo il 30% di coloro che avevano seguito la strategia Step-up avevano raggiunto la guarigione mucosale al termine del secondo anno di trattamento (quindi l’OR per la guarigione mucosale era di oltre 6 volte a favore della strategia Top-down), pur avendo simili probabilità di essere in uno stato di remissione clinica. <br /> Tuttavia seguendo i pazienti per ulteriori 2 anni (ed avendo ridotto la popolazione ai 49 soggetti con valutazione endoscopica all’anno 2 di terapia), coloro che avevano raggiunto la guarigione mucosale, con qualsiasi regime e farmaco, presentavano rispetto a coloro che non avevano ottenuto la guarigione mucosale una probabilità circa 6.5 volte maggiore di conservare una remissione clinica senza steroidi, 7.5 volte maggiore di conservare una remissione clinica senza sia gli steroidi, sia IFX e un rischio ridotto di quasi 7 volte di sviluppare nuove fistole nei 2 anni successivi <br />
  • In ogni caso va ricordato che la malattia di Crohn può avere un decorso quanto mai variabile e lo studio epidemiologico di popolazione norvegese dell’IBSEN ha registrato che valutando i pannelli in senso orario: <br /> poco meno di metà dei pazienti ha un decorso progressivamente meno invalidante, con relapse sempre meno frequenti e gravi rispetto al primo episodio <br /> circa 1/5 dei casi ha un decorso cronicamente attivo <br /> in 1/3 dei casi circa ha episodi nel tempo di eguale gravità rispetto al primo, intervallati da periodi di remissione <br /> in casi relativamente eccezionali, a un decorso iniziale assai mite segue una progressione verso un’attività di malattia grave e persistente. <br /> Di conseguenza ogni trattamento deve essere individualizzatro tenendo conto delle caratteristiche di ciascun paziente. <br />

Onali S. IBD: Cosa è cambiato nella Terapia. ASMaD 2013 Presentation Transcript

  • 1. HOT TOPIC IN GASTROENTEROLOGIA 2013 TEN TOPIC IN TEN MINUTES IBD: cosa è cambiato nella terapia. Sara Onali, MD, PhD U.O.C. di Gastroenterologia Dipartimento di Medicina dei Sistemi Università di Roma Tor Vergata
  • 2. INFLAMMATORY BOWEL DISEASE CROHN’S DISEASE • Can involve all gut • Transmural inflammation • Focal lesions • Post-operative recurrence ULCERATIVE COLITIS 10% Undefinited colitis • Involve rectum-colon • Mucosal inflammation • Continuous lesions • No recurrence
  • 3. EPIDEMIOLOGY • Increase incidence 1980-90 • Bimodal incidence 15-40/60 • No difference between sex • Increase incidence among Askenatzi
  • 4. The European Crohn’s & Colitis Organization’s Epidemiological Committee study (ECCO-EpiCom) recently investigated the occurrence of IBD in Europe (2010). Prevalence of IBD 2.5– 3 million people in Europe and 1–1.5 million in North America Incidence rates 0.1–20.2 for CD and 0.5–31.5 per 100 000 p-yrs in UC Munkholm et al Curr Opin Gastroenterol 2013
  • 5. Pathophysiology of IBD: Complex and multifactorial disease Intestinal inflammation due to an unappropriated response to gut microbiota in genetically predisposed subject
  • 6. Remission Inflammatory flare Natural history of IBD Pariente B Inflamm Bowel Dis 2012
  • 7. Clinical approach to the management of IBD Disease subtype Goals Patient’s needs
  • 8. Clinical approach to the management of IBD PREREQUISITES FOR MEDICAL TREATMENT Site(s) Disease subtypes Extent localized – segmental extensive Behaviour Drugs Disease activity Patients’ needs Goals Options
  • 9. ULCERATIVE COLITIS: CLINICAL PATTERNS BY SITE/EXTENT Endoscopic Montreal classification a. Ulcerative proctitis (limited to the rectum) b. Left-sided colitis (up to the splenic flexure) c. Extensive colitis EXTENSIVE COLITIS LEFT-SIDED COLITIS DISTAL COLITIS Satsangi et al, Gut 2006. Gasche C, Inflamm Bowel Dis 2000.
  • 10. CROHN’S DISEASE SUBGROUPING: Crohn’s colitis Non StricturingNon penetrating Stricturing Penetrating
  • 11. CROHN’S DISEASE SUBGROUPING: Crohn’s ileitis Non Penetrating-non stricturing Stricturing Penetrating
  • 12. Clinical approach to the management of IBD The many goals of medical treatment Inducing remission Goals Maintaining remission Meeting specific Goals Preventing/treating complications Mucosal healing/deep remission
  • 13. Clinical approach to the management of IBD Defining variables Crohn’s Disease Remission: Patients with a CDAI <150. Response: A ΔCDAI of ≥−100 points. Ulcerative colitis Remission: Complete resolution of symptoms and endoscopic mucosal healing....in clinical practice meant a stool frequency ≤3/day with no bleeding and no urgency. Responce: Decrease in the activity index of 30%, plus a decrease in the rectal bleeding and endoscopy subscores Sandborn Gastroenterology 2002 D’Haens Gastroenterology 2007
  • 14. Clinical approach to the management of IBD: A Treatment Pyramid based on Severity Drugs Severe Anti-TNF strategies Surgery 6MP/AZA /MTX Moderate Systemic Corticosteroids Mild Non-systemic Steroids Antibiotics/Probiotics Aminosalicylates
  • 15. Inducing remission in CD Adapted from Travis SPL et al Gut 2006 Indication Drug EL Rec. grade Mild active IC Mild active C Budesonide Salazopyrin 2a 1b B A Moderate active IC Budesonide AZA/6MP Syst. steroids 1a 1a A A Moderate relapsing Steroids + in Anti Tnf-s AZA/6MP pts selected 1a B Severe IC Steroids +/Anti Tnf-s AZA/6MP Anti TNFs+/-ISS 1a A B 1b B Severe relapsing Steroid refractory/ dependent Distal colitis Topical 5ASA 5 D Poor prognosis pts early introduction of ISS, MTX and or anti-TNF therapy [EL5 RG D]. All currently available anti-TNF appear to have generally similar efficacy and adverse-event profiles for inflammatory (‘luminal’) Crohn's disease, the choice depends on availability, route of delivery, patient preference, cost and national guidelines [EL5, RG D]. Dignass et al JCC 2010
  • 16. Rate of remission of anti-TNFά therapy for CD INFLIXIMAB ACCENT I (remission rates at 4 wks) (Response rates 4 wks) Infliximab vs PL 33% vs 4% P=0.01 Infliximab vs PL 65% vs 417% P=0.01 Hanauer SB Lancet 2002. ACCENT II (remission rates at 54 wks) (Response rates at 54 wks) Infliximb vs PL 23% vs 19% P<0.01 Infliximb vs PL 46% vs 23% P<0.01 Sands BE, Clin Gastroenterl Hepatol 2004. CERTOLIZUMAB PRECISE I Certolizumab Pegol vs PL 35% vs 27% P=0.02 at Wks 6 Certolizumab Pegol vs PL 23% vs 16% P=0.02 at wks 26 PRECISE I Certolizumab Pegol vs PL 48% vs 29% P<0.001 at Wks 26 Sandborn WJ, N Engl J Med 2007. Schreiber S N Engl J Med 2007.
  • 17. Rate of remission of anti-TNFά therapy for CD ADALIMUMAB CLASSIC I (remission rates at 4 wks) 40mg/20mg vs PL 18% vs 12% P=0.36 80mg/40mg vs PL 24% vs 12% P=0.6 120mg/80mg vs PL 36% vs12% P=0.01 CLASSIC I (response rates at 4 wks) 40mg/20mg vs PL 54% vs 37% P<0.05 80mg/40mg vs PL 59% vs 37% P=0.01 120mg/80mg vs PL 59% vs 37% P=0.01 Hanauer SB et al.Gastroenterology 2006. CLASSIC II (remission rates at 56 wks) 40mg eow vs PL 79% vs 44% P<0.05 40mg ew vs PL 83% vs 44% P<0.05 CLASSIC II (response rates at 56 wks) 40mg ew vs PL 89% vs 72% P<0.05 Sandborn WJ et al Gut 2007. CHARM (remission rates in maintenance) 26 wks 56wks 40mg eow vs PL 40% vs 17% P<0.01 40mg eow vs PL 40% vs 17% P<0.01 40mg ew vs PL 47% vs 17% P<0.01 40mg ew vs PL 47% vs 17% P<0.01 Colombel JF et al. Gastroenterology 2007.
  • 18. Inducing remission in UC Site Proctitis Indication Mildmoderate Refractory Left-side Mildmoderate Drug EL Rec.grade 5 ASA topic/os 1b A ISS/Biol C 4 B Steroids Nn resp ASA 5 ASA topic/os 1b 1b C 1b B Steroids Severe Extensive Mildmoderate ACT 1 Clinical Remission at Week 8 and Week 30 *p<0.001 †p=0.002 ‡p=0.001 5 ASA topic+os 1a Steroids Non responder 1b ISS/anti TNF A C 38.8* 32.0 † Week 8 Placebo 1b 33.9 ‡ 36.9* 15,7 14,9 Anti Tnfs/CYS ) % ( s e a f n i t p o r P Severe Steroid dependence/refractory 100 90 80 70 60 50 40 30 20 10 0 Week 30 5 mg/kg Infliximab B 10 mg/kg Infliximab Dignass et al JCC 2012
  • 19. Maintaining remission
  • 20. MAINTAINING REMISSION IN CROHN’S DISEASE Mantenance with oral 5-ASA is a treatment option (EL5, RG D), but there is no Mantenance with oral 5-ASA is a treatment option (EL5, RG D), but there is no evidence for its efficacy[EL1b, RG B]. The odds ratio for 6 studies where evidence for its efficacy[EL1b, RG B]. The odds ratio for 6 studies where participants were followed up for 12 months was 1.00 (95%CI 0.80-1.24). participants were followed up for 12 months was 1.00 (95%CI 0.80-1.24). C Prantera, F Pallone et al, Gastroenterology 1992, 103, 363-368 Akobeng AK, Cochrane Database Syst Rev 2005 Akobeng AK, Cochrane Database Syst Rev 2005 If remission has been achieved with CS, thiopurine [EL1a, RG A] or methotrexate [EL1b, RG A] should be considered. If remission has been achieved with an anti-TNF agent, maintenance with regular anti-TNF therapy should beconsidered [EL1b, RG B]. Azathioprine may be considered in combination with anti-TNF therapy or is an option as monotherapy if naïve to thiopurines [EL2b, RG C]. Dignass et al JCC 2010
  • 21. Maintenance remission in UC The goal of maintenance therapy in UC is to maintain steroid-free remission, clinically [EL1, RG A] and endoscopically defined [EL2, RG B] Major determinants • Disease extent [EL1b, RG B] • Disease course (frequency of flares) [EL5, RG D] • Failure of previous maintenance treatment [EL5, RG D] • Severity of the most recent flare [EL5, RG D] • Treatment used for inducing remission during the most recent flare [EL5, RG D] • Safety of maintenance treatment [EL1b, RG B] • Cancer prevention [EL2a, RG B] Dignass et al JCC 2012
  • 22. Maintenace remission in UC Oral 5-ASA are the first line maintenance treatment in pts responding to 5-ASA or steroids (oral or topical) [EL1a, RG A] Maintenance with topical 5-ASA is an alternative in proctitis/left-sided colitis [EL1b, RG A] AZA/6MP is recommended in mild-moderate disease with early or frequent relapse or intolerant to 5-ASA [EL5, RG D], in steroid-dependent [EL1a, RG A ]. Pts with severe colitis responding to intravenous steroids, intravenous ciclosporin or infliximab, AZA/6MP should be considered to maintain remission [EL2b, RG3] In pts responding to anti-TNF agents, both maintaining remission withAZA/6MP [EL4, RGC] and continuing anti-TNF therapy with or without thiopurines [EL1a, RGA]. Pts responding to infliximab continuing infliximab is also appropriate [EL4, RGC]
  • 23. Mucosal healing/ Mucosal healing/ deep remission deep remission
  • 24. Mucosal healing and deep remissione as new goal?? There is no validated definition of MH in IBD The „ideal“ definition of Mucosal Healing (MH) could be complete endoscopic healing of all inflammatory and ulcerative lesions of the gut mucosa in CD and UC In CD, an endoscopic response to treatment can be defined as “absence of ulcers” or a significant change of endoscopic disease activity score (CDEIS or SES-CD). In UC, an endoscopic response to treatment can be defined as a significant change of endoscopic disease activity score (Baron score or Mayo endoscopic subscore). Crohn’s disease Pineton de Chambrun G, et al. Nat Rev Gastroenterol Hepatol 2010. Ulcerative colitis
  • 25. • Symptom Improvement with Mucosal Healing D’Haens et al. Gastroenterology 1999 • Mucosal Healing in CD at Year 2 Predicts Sustained Clinical Remission 49 pts from SUTD trial underwent colonoscopy at yrs 2 and were followed-up through year 3 and 4 Baert F, et al. Gastroenterology 2010
  • 26. Treatment goal Goal Clinical Parameters Outcomes Response Improved symptoms Improved QoL No symptoms Remission Normal labs Deep remission Normal endoscopy Histological remission SUSTAINED REMISSION Decreased hospitalisation No surgery Minimal/no disability
  • 27. Clinical approach to the management of IBD 1. Immunosuppressors (AZA-6MP) are effective in the long term. 2. No evidence for a role of 5-ASA in the maintenance of remission in CD. 3. Infliximab and other anti-TNF drugs are rapidly effective in most cases and the use of biologics is expanding. 4. Mucosal healing may be achieved. More important in UC.
  • 28. State of art for biological therapy for CD Target Compound Stage of development TNF-ά Infliximab Gov. Approval TNF-ά Adalimumab Gov. Approval TNF-ά Certolizumab Pegol US Gov. Approval TNF-ά Golimumab Phase III ά4integrin Natalizumab US Gov.approval ά 4β7-integrin Vedolizumab Phase III IL 12/23 ABT-874 Phase II IL 12/23 Ustekinumab Phase II IL-6 receptor Tocilizumab Phase II CD3 N1-0401-01 Phase I/IIa CD40 Ch5D12 Phase I CTLA-4 Abatacept Phase III CD20 Rituximab Phase III IL-17 AIN457 Phase II
  • 29. However… Management Must Be Tailored to the Individual Patient Disease activity 43% 0 19% IBSEN: disease course in Crohn’s disease over 10 years 32% 3% Years 10 0 Years Solberg IC, et al. Clin Gastroenterol Hepatol 2007;5:1430–8 10 Missing data, 3% We must intervene with anti-TNF early in: • Extensive small bowel disease • Younger patients • Severe upper GI disease • Patients with perianal lesions • Severe rectal disease • Patients with early stricturing / penetrating disease • Patients with deep colonic ulcers Beaugerie L, et al. Gastroenterol 2006;130:650–6
  • 30. A patients’ needs oriented approach to the management An alternative explanation for symptoms other than active disease should always Options be considered (Infection, bacterial overgrowth, bile salt malabsorption, gallstones may also cause symptoms in patients with known Crohn’s colitis). Prevalence of Functional Gastrointestinal Disorders (FGD) in IBD IBD (n=361) N % (95% CI) CD (n=239) N % (95% CI) UC (n=122) N % (95% CI) No FGD 38 10.5 ( 7.4-13.7) 23 9.7 ( 5.9-13.3) 15 12.3 ( 6.4-18.1) >1 FGD 323 89.5 (86.3-92.6) 216 90.4 (86.6-94.1) 107 87.7 (81.9-93.5) 124 94.7 (90.8-98.5) 74 94.9 (89.9-99.8) All patients Patients with active disease >1 FGD 198 94.7 (91.6-97.8) Patients with inactive disease >1 FGD 122 81.9 (75.7-88.0) *Inactive CD vs. Inactive UC, p=0.17 89 84.8 (77.9-91.6)* 33 75.0 (62.2-87.8)* Irvine EJ et al 2005