Impatto della terapia biologica sul decorso clinico della M. di Crohn - Gastrolearning®
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Gastrolearning I lezione Impatto della terapia biologica sul decorso clinico della M. di Crohn - Prof. F. Pallone (Università di Roma Tor Vergata) www.gastrolearning.it
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Impatto della terapia biologica sul decorso clinico della M. di Crohn - Gastrolearning®
- 1. Were do we stand with solid evidence for biologics in Crohn’s Disease Evidence Clinical relevance Biological plausibility
- 2. Biologic plausibility, pipeline Do all patient equally benefit from available biologics Goals of therapy Do biologics change the course and natural history of CD Problems and pitfalls in biologics therapy for CD
- 3. Biologic plausibility, pipeline Do all patient equally benefit from available biologics Goals of therapy Do biologics change the course and natural history of CD Problems and pitfalls in biologics therapy for CD
- 4. Dissecting mechanisms of inflammation in IBD by ex-vivo studies MacDonald TT & Monteleone G, Science 2005;307:1920-5
- 5. Therapeutic pipeline in Crohn’s disease e in s ok or m t he hibi C n cytokine i blockers ulator omod Cell adhesion molecule n Inhibitors Immu JAK r Inh ibito TNF Stem Cell blockers therapies Adapted from Danese et al GUT 2012
- 6. Learning from other chronic inflammatory disorders Presumed pathogenetic pathways involved in rheumatoid arthritis
- 8. Inhibition of IL-17A by anti-IL-17A monoclonal antibody secukinumab is ineffective in moderate to severe Crohn’s disease Secukinumab 2 x 10 mg/kg i.v. Placebo 50 50 (>100 points drop in CDAI Remission at week 6 (%) Response at week 6 (%) 40 40 (CDAI < 150) 30 30 30 20 20 18 10 10 15 10 0 0 Hueber et al. Gut 2012
- 9. Augmentation of Tregs to treat human autoimmunity: In vivo and ex vivo approaches to enhance the relative numbers of Tregs
- 10. Different type cytokines are mutually antagonistic, and one or the other subtype may be dominant at any one time during immune responses Th2 Th2Th2 IL-4 IFN/TNF IL-17 Monteleone G et al Trends in Pharmacology 2011
- 11. Inhibition of IFN-γ enhances Th2 and Th17-type cytokines Th2 Th2 Th2 IL-4 Fontolizumab Th17 Th1 IFN-γ IL-17 Th17 Th1 Th1 Th17 Monteleone G et al Trends in Pharmacology 2011
- 12. Inhibition of IL-17A enhances Th1-type cytokines Th2 Th2 Th2 IL-4 Secukinumab Th17 Th1 IFN-γ IL-17 Th17 Th1 Th1 Th17 Monteleone G et al Trends in Pharmacology 2011
- 13. Targeting immune pathways in IBD: lessons from unsuccessful data Redundancy of soluble Block multiple signals cytokines, chemokines simultaneously or and inflammatory pathways sequentially Positive effect of an anti- cytokine neutralizing strategy Reconsider the use of in mice may not necessarily murine models of be translated in humans colitis Success of currently avaliable biologics in CD is mostly Target of available dependent on their killing biologics are cells action against pro- (T cells/ macrophages), inflammatory cells not soluble cytokines
- 14. Biologics for Crohn’s Disease Chimeric Human monoclonal monoclonal antibody antibody Fc IgG1 Infliximab Adalimumab mAb mAb
- 15. Biologic plausibility, pipeline Do all patient equally benefit from available biologics Goals of therapy Do biologics change the course and natural history of CD Problems and pitfalls in biologics therapy for CD
- 16. Were do we stand with solid evidence for biologics in Crohn’s Disease Disease Disease heterogeneity complexity Uncertainty Disagreement
- 17. UNMET NEEDS FOR AN EBM BASED THERAPY IN CD Measuring Biomarkers intestinal damage Disease & bio-profiling behaviour Do all pts Tailored need therapy treatment?
- 18. AVALABLE TOOLS FOR DISEASE ASSESSMENT IN CD Defining disease subtypes and treatment goals LC PTV 05 a “VISUAL” approach DB PTV 07
- 19. IS THE “VISUAL” APPROACH ADEQUATE FOR DEFINING TREATMENT OPTIONS AND OUTCOME MEASURES?
- 20. Management Must Be Tailored to the Individual Patient IBSEN: disease course in Crohn’s disease over 10 years 43% 19% Disease activity 3% 32% 0 Years 10 0 Years 10 Solberg IC, et al. Clin Gastroenterol Hepatol 2007;5:1430–8 Missing data, 3%
- 21. Long-term evolution of Crohn’s disease behaviour Start therapy 100 Cumulative probability of remaining free of 90 80 70 complications (%) 60 Penetrating 50 40 Inflammatory 30 Stricturing 20 10 0 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240 Patients at risk: Months n= 2,002 552 229 95 37 Cosnes J, et al. Inflamm Bowel Dis 2002;8:244–50
- 22. Evolution of Crohn’s disease behaviour over 10 years Behaviour categories of the Vienna classification according to site AT DIAGNOSIS AFTER 10 YEARS L1 L2 L3 L1 L2 L3 B1 76.9 72.1 69.7 B1 37.3 28 22.9 B2 14.9 1.5 15.2 B2 43 20 17 B3 8.3 26.5 15.2 B3 19.6 52 60 L1 pure ileal B1 non stricturing-non penetrating L2 pure colonic B2 stricturing L3 ileo-colonic B3 penetrating adapted from Louis E et al Gut 2001;49:777–782
- 23. Remission and response from control arms of trials of biological therapies for active luminal Crohn’s disease 18 % remission 33 % response Tinè F et al Aliment Pharmacol Ther 27, 1210–1223
- 24. When to Intervene early with aggressive therapy: Poor Prognosis Patients We must intervene with immunosoppresive drugs early in: • Extensive small bowel disease • Severe upper GI disease • Severe rectal disease • Younger patients • Patients with perianal lesions • Patients with early stricturing / penetrating disease • Patients with deep colonic (rectal) ulcers
- 25. Biologic plausibility, pipeline Do all patient equally benefit from available biologics Goals of therapy Do biologics change the course and natural history of CD Problems and pitfalls in biologics therapy for CD
- 26. What is Deep Remission?
- 27. Decision patterns in Crohn’s Disease Based on 479 consecutive CD patients attendances GROSS CLINICAL HUMORAL CHANGES “ACTIVITY” * “ACTIVITY” § Pattern 1 − − − optimal Pattern 2 − − + Pattern 3 + − − enough Pattern 4 + − + acceptable ? Pattern 5 − + − Pattern 6 − + + Pattern 7 + + − Pattern 8 + + + * + = CDAI > 150 or Simple Index > 3 § + = CRP > 1.5 mg/dl and/or ESR > 25 Torsoli A et al, Ital J Gastroenterol, 1983, 15, 138-139
- 28. Mucosal Healing in CD There is no validated definition of Mucosal Healing (MH) in CD patients The “ideal„ definition of MH could be complete endoscopic healing of all inflammatory and ulcerative lesions of the gut mucosa in CD No endoscopic indices have validated a cut-off value for MH Pineton de Chambrun G et al. Nat Rev Gastroenterol Hepatol 2010 Armuzzi A et al. JCC 2012
- 29. A new therapeutic end point in the management of CD Deep Remission Is a recently introduced end point, which includes corticosteroid free remission and mucosal healing It has been introduced and applied to patients with CD on biologics or immunomodulators who have no symptoms and objective signs of inflammation Rutgeerts P et al. Gastroenterology 2012
- 30. Mucosal Healing in CD before anti TNF-α after anti TNF-α
- 31. Biologic plausibility, pipeline Do all patient equally benefit from available biologics Goals of therapy Do biologics change the course and natural history of CD Problems and pitfalls in biologics therapy for CD
- 32. DO BIOLOGIS IMPACT ON THE NATURAL HISTORY OF CROHN’S DISEASE ? Early disease Chronic uncomplicated disease course Complicated disease
- 33. DO BIOLOGIS IMPACT ON THE NATURAL HISTORY OF CROHN’S DISEASE ? Early disease Chronic disease course free of either complications and major symptoms Complicated disease
- 34. Inflammatory Activity and Progression of Damage in a Theoretical Patient with CD Stricture Surgery Inflammatory activity (CDAI, CDEIS, CRP) Digestive damage Fistula/abscess Stricture Disease Diagnosis Early onset disease Pariente B et al. Inflamm Bowel Dis. 2011;17(6):1415.
- 35. Infliximab Improves Clinical Remission and Allows for Mucosal Healing All randomized patients Week 54 results Clinical remission Complete mucosal healing ACCENT I – Hanauer SB, et al. Lancet 2002
- 36. Patients with Corticosteroid-free Clinical Remission and Mucosal Healing at Week 26 Colombel JF et al N Engl J Med 2010;362:1383-95.
- 37. EXTEND: Deep Remission with Adalimumab Adalimumab, induction-only (placebo) 25 Adalimumab, every other week p<0.001 Patients with deep remission (%) p=0.34 19.4 20 16.1 15 9.8 10 5 6/61 10/62 0/61 12/62 0 Week 12 Week 52 Deep remission defined as clinical remission (Crohn’s Disease Activity Index [CDAI] <150) and mucosal healing (absence of mucosal ulceration) Colombel JF, et al. J Crohn’s Colitis 2010;4:S11
- 38. EXTEND Deep Remission at Week 12 is Associated with Better Quality of Life at Week 52 IBDQ remission at week 52 75 Week 52 IBDQ remission (%) 64 Patients achieving deep remission are more likely to have IBDQ remission 50 (p<0.05) 26 25 7/11 14/53 0 Deep remission Non-deep remission1 (Wk 12) (Wk 12) 1 Logistic regression adjusted baseline IBDQ score IBDQ remission = IBDQ≥170 Colombel JF, et al. UEGW 2010, Barcelona, Spain, October 23-27:OP371
- 39. Mucosal Healing after 1 Year and Risk of Surgery ULCERATIVE COLITIS CROHN’S DISEASE HR = 0.34 (0.14-0.86) p=0.02 HR = 0.42 (0.20-0.89) p=0.027 1.00 1.0 MH Proportion of patients Proportion of patients 0.9 not colectomised 0.96 3.4% MH not resected 0.8 16.9% 0.94 0.7 No MH 0.90 9.7% 0.6 No MH 31.0% 0.5 0.86 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 Years since 1-year visit Years since 1-year visit Soldberg IC, et al. Scand J Gastroenterol 2009
- 40. Infliximab Scheduled Therapy Results in Fewer Surgical Procedures P<0.05 P<0.05 N=143 N=139 N=99 N=96 * Surgery major enough to categorise a patient as a treatment failure in the trial, excluding drainage of abscesses, seton placement and stricture dilation. Lichtenstein GR, et al. Gastroenterology 2005
- 41. Adalimumab: Reduction in Hospitalisation Risk 78% reduction in Crohn’s-related hospitalisation at 3 months The difference was apparent 2 weeks after randomisation 57% relative risk reduction at 12 months 30 Placebo hospitalisation risk (%) Adalimumab Crohn’s-related 20 Week 2 Log-rank test: risk was significantly different (p<0.01) 10 n=499; CHARM 0 0 50 100 150 200 250 300 350 Days since randomisation Feagan BG, et al. Gastroenterology 2007;
- 42. Clinical Practice Experience: Leuven CD Real-Life Data CD Cohort: 63.4% With Sustained Clinical Benefit Median Follow-up 55 Months1 63.4% 1 Schnitzler F, et al. Gut. 2009;58:492-500; 2Ferrante M, et al. J Crohn’s Colitis. 2008;2:219-225.
- 43. Biologic plausibility, pipeline Do all patient equally benefit from available biologics Goals of therapy Do biologics change the course and natural history of CD Problems and pitfalls in biologics therapy for CD
- 44. Clinical trial patients Adult age and virtually any disease duration Clinical activity (symptoms scoring) SOP responsive/refractor y Concomitant treatment
- 46. DO BIOLOGIS IMPACT ON THE NATURAL HISTORY OF CROHN’S DISEASE ? Early disease Chronic uncomplicated disease course Complicated disease
- 47. Immune cells: key players of the IBD-associated tissue damage Dendritic cell T0 TLRs T MHC-1/2 B7 T- 3 IL-4 -2 be IL TSLP, t TGF-β, IL-15 TH2 T2 T1 TH1 Macrophage T2 TH2 MMP RA T17 TH17 T2 TH2 TH1 TH1 T1 T1 TLRs IL-8 TH17 TH17 T17 T17 IL-5 NOD2 CD103+ mTNF sis IL-8 Ulcer/ pto IL-13 IFN-γ TIMP fistula po TNF-α ↓a IL-12 IL-17 T T1 T 1 ↑collagen TH1 Treg TH1 H1 TH1 T1 T1 T1 TH1 TH1 TH1 deposition T1 T TH1T T TH1 H1 TH1 T1 1 1 TH1 TH1 T T1 T Scar H1 1 Fibrosis TH1 T1 tissue T H1 TH T H1 1 T cells Blood vessel TLRs CD40
- 48. Star wars Naive T cell CD4 - CD8 - IL-2 IL-12 IFN-γ CD4+ STAT4 Th0 IL-10 IFN-γ Th1 CD4+/CD25+ TGF-β IL-2 IL-18 FOXP3 IL-23 IL-13 IL-17 Th2 IL-4 Th17 IL-22 IL-5 IL-6
- 50. COMBINING EX VIVO DATA WITH CLINICAL EVIDENCE EARLY CD LATE CD IL17A IL1β,IL6,IL23 Th17 IL17F ? APC Th1/Th17 IFNγ IL17 IL1 TNFα 2 IL1β IL6 Th1 IL18 IFNγ TNFα IL21 Zorzi F et al FISMAD 2011
- 51. Infliximab prevents Crohn’s disease recurrence after ileal resection Endoscopic score after 1 year of resection Grade 0-1 Grade 2-4 11/13 10/11 10 10 2/13 1/11 INFLIXIMAB PLACEBO INFLIXIMAB PLACEBO Regueiro M et al GASTROENTEROLOGY 2009;136:441–450
- 53. Range 15-54% Gisbert JP and Panes J. Am J Gastroenterol 2009
- 54. Maintenance of Remission Among Patients With Crohn’s Disease on Antimetabolite Therapy After Infliximab Therapy Is Stopped 52 relapses in 115 patients Median (±SE) follow up 21 ± 1 mo LOUIS E et al GASTROENTEROLOGY 2012;142:63–70
- 55. TREAT Registry: Serious Infections Logistic Regression Data (Multivariate) Odds Ratio 95% CI Age (years) 1.01 0.99-1.03 Female 1.24 0.81-1.90 Moderate or severe CD 2.11 1.10-4.05* Current use of infliximab 1.40 0.95-2.07 Current use of 6MP/AZA/MTX 0.88 0.61- 1.27 Current use of corticosteroids 2.21 1.46- 3.34* Current use of narcotic 2.38 1.56- 3.63* analgesics *P < .05 Lichtenstein GR, et al. Clin Gastroenterol Hepatol. 2006
- 56. Advanced Age Is an Independent Risk Factor for Severe Infections and Mortality in Patients Given Anti–Tumor Necrosis Factor Therapy for Inflammatory Bowel Disease
- 58. Cost Distribution for Crohn’s Disease A Minority of patients Account for the Majority of Costs 100 100% 90 90% 80 80% 70 70% 60 60% % Cost 50 50% 40 41% 30 31% 20 20% 10 12% 5% 0 0 10 20 30 40 50 60 70 80 90 100 % All Patients Feagan BG et al. Am J Gastroenterol. 2000;95:1955.
- 63. Yanai H and Hanauer SB. Am J Gastroenterol 2011
- 64. 5-ASA Brand name Cover Release Site Asacol Eudragit S pH>7 Colon ± terminal ileum Salofalk Eudragit-L pH>6 Colon + ileum Mesasal Eudragit-L pH>6 Colon + ileum Pentasa Ethylcellulose Time and Colon + ileum+ jejunum pH-dependent Mesavancol MMX pH Colon Immunomodulators Corticosteroids Drugs AZA Oral Intravenous Topical (suppository, foam, enema) Prednisolone Hydrocortisone Hydrocortisone 6-MP Prednisone Metyl-prednisolone Prednisolone metasulfobenzoato Budesonide Budesonide 6-TG Beclomethasone Beclomethasone diproprionate dipropionate Biological agents
- 65. Mucosal Healing in CD There is no validated definition of Mucosal Healing (MH) in CD patients The “ideal„ definition of MH could be complete endoscopic healing of all inflammatory and ulcerative lesions of the gut mucosa in CD No endoscopic indices have validated a cut-off value for MH Pineton de Chambrun G et al. Nat Rev Gastroenterol Hepatol 2010 Armuzzi A et al. JCC 2012
- 66. Clinical Practice Experience: Leuven CD and UC Real-Life Data CD Cohort: UC Cohort: 63.4% With Sustained Clinical Benefit 68% With Sustained Clinical Response Median Follow-up 55 Months1 Median Follow-up 33.4 Months2 68% 63.4% 1 Schnitzler F, et al. Gut. 2009;58:492-500; 2Ferrante M, et al. J Crohn’s Colitis. 2008;2:219-225.
- 67. Clinical trial patients Any adult age and virtually any disease duration
- 68. CHARM / ADHERE: Remission Sustained through 3 Years CHARM 6 mo 12 mo 24 mo 36 mo baseline Open label extension (OLE) 100 100 100 85 with remission (%) 78 81 84 83 77 80 72 64 Patients 60 40 20 145 145 113/145 118/145 111/145 123/145 105/145 122/145 93/145 120/145 0 Week 56 Week 24 Week 48 Week 60 Week 108 CHARM ADHERE ADHERE ADHERE ADHERE All adalimumab, NRI All adalimumab, LOCF Pts randomised to ADA, in remission (CDAI<150) at week 56 of CHARM, and enrolled in OLE ITT (n=145). LOCF: last observation carried forward; NRI: non-responder imputation. 467 patients enrolled in the open-label extension (ADHERE) Panaccione R, et al. J Crohn’s Colitis 2009;3:S69-70
- 69. D’Haens G, et al. Lancet 2008
- 70. Colombel JF et al NEJM 2010
- 71. Discontinuation of Infliximab in Patients in Stable Remission on Combination Therapy (Azathioprine Maintained) 79±4% 56±5% 50±5% 52 relapses in 115 patients Median (±SE) follow up 21 ± 1 mo # at risk : 115 102 79 63 51 47 39 27 20 12 9 Louis E et al. Gastroenterology ,2009;136(Suppl 1):A-146, Gastroenterology epub 2011.
- 72. NATURAL HISTORY OF CROHN’S DISEASE A decades long history Early disease
Notas del editor
- A CONCEPT AND A FEW NEW TOOLS
- Crohn's disease may have a variable course. The IBSEN study, a Norvegian population epidemiological study showed that in 43 % patients have a progressively less disabling course with relapses less frequent and severe than the first episode. about 19 % of the cases has a chronically activecourse. in 1/3 of cases has episodes of equal severity compared to the first Consequently, each treatment must be individualized taking into account the characteristics of each patient 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: poco meno di metà dei pazienti ha un decorso progressivamente meno invalidante, con relapse sempre meno frequenti e gravi rispetto al primo episodio circa 1/5 dei casi ha un decorso cronicamente attivo in 1/3 dei casi circa ha episodi nel tempo di eguale gravità rispetto al primo, intervallati da periodi di remissione in casi relativamente eccezionali, a un decorso iniziale assai mite segue una progressione verso un’attività di malattia grave e persistente. Di conseguenza ogni trattamento deve essere individualizzatro tenendo conto delle caratteristiche di ciascun paziente.
- As we know, Crohn’s disease is a progressive disease that leads to cumulative damage and disability. One thing is to start treatment at this stage and another thing is to start treatment at another time, in this time for exemple The evidence from EXTEND suggests that deep remission is associated with improved longer-term outcomes. Let us now turn our attention to further long-term benefits that may be achieved with extended treatment. As we know, Crohn’s disease is a progressive disease that leads to cumulative damage and disability. These familiar Kaplan-Meier curves are based on a retrospective analysis of data from 2,002 Crohn’s disease patients. The curves estimate the probabilities of remaining free of penetrating complications (upper curve) and of penetrating and/or stricturing complications (lower curve). This analysis revealed that only 48% and 12% of patients would be free of these complications 5 and 20 years after diagnosis, respectively.
- But How
- Qual è o quali possono essere le definizioni di deep remission? Un nuovo obiettivo terapeutico che si sta imponendo nella comunità scientifica è rappresentato dalla cosidetta remissione profonda, che è già stata definita come la combinazione della remissione clinica (CDAI < 150), in assenza di utilizzo residuo di steroidi, unitamente a ulteriori variabili oggettive, come la negatività degli indici di attività biologica di malattia (PCR) e/o in associazione eventuale alla remissione endoscopica.
- Sempre nello studio ACCENT I si osserva pressoché totale normalizzazione di attività clinica (a sinistra), che va di pari passo con la guarigione delle lesioni mucosali (a destra). I grafici sottolineano la superiorità però del regime schedulato rispetto al trattamento episodico con IFX. Se nell’ambito clinico la differenza, pur significativa, appare meno rilevante, dal punto di vista della guarigione mucosale il dato è più marcato: il regime episodico, pur ottenendo una remissione clinica all’anno dell’ordine del 30%, non significativamente inferiore a livello puntuale rispetto al regime schedulato, determina guarigione mucosale solo in 18% dei casi trattati ed inclusi nel sottostudio endoscopico, mentre il regime schedulato attesta sua efficacia al 44%, con OR di 3.6. Si noti che l’osservazione è limitata dal fatto che l’analisi basata sui dati clinici include l’intera coorte dell’ACCENT I (oltre 500 pazienti), mentre il dato dell’endoscopia alla settimana 54 è disponibile solo per 58 pazienti, e va pertanto contestualizzato e preso con le dovute cautele.
- Dallo studio EXTEND si possono ricavare dati post-hoc sulla deep remission , qui definita come remissione clinica (CDAI <150)+ guarigione mucosale. La deep remission all’anno è significativamente più frequente nei soggetti trattati continuativamente con adalimumab, rispetto a quelli trattati con placebo, anche se è registrata solo in circa 1/5 dei casi. Volendo quantificare la magnitudine della differenza essa all’anno corrisponde a un valore di OR = 30.4 (95%CI 1.8-527). Al terzo mese, invece, esiste ancora un effetto carry-over dell’induzione per cui, anche nel braccio in mantenimento con placebo, quasi il 10% dei pazienti risponde ai criteri per definire la deep remission .
- D’altra parte la proporzione di pazienti con IBDQ uguale o superiore al cut-off di 170 punti, corrispondente al valore riscontrato nei soggetti in remissione di malattia, all’anno di trattamento con adalimumab è significativamente superiore in coloro che avevano raggiunto la remissione profonda già dalla settimana 12. In questo caso il valore di OR è 4.88 (95%CI 1.24-19.22). Si noti che in quest’analisi si utilizza la stratificazione per deep-remission alla settimana 12 nei soli pazienti trattati con farmaco attivo, sono esclusi i soggetti in placebo.
- Lo studio di popolazione scandinavo del gruppo IBSEN (si tratta in realtà di un dato collaterale, raccolto con un sistema di score non validato né riprodotto ed unico per Crohn e Colite Ulcerosa) ha dimostrato che i pazienti che ad un anno dalla diagnosi presentavano un quadro endoscopico silente e migliorato, a prescindere dal regime terapeutico che aveva indotto tale miglioramento, mostravano un rischio significativamente inferiore di proctocolectomia (per i pazienti con colite ulcerosa - a sinistra- si osserva una riduzione del rischio di 2/3) o di interventi chirurgici resettivi (per i pazienti con Crohn - a destra - si osserva una riduzione del rischio di oltre la metà). Il dato ha particolare rilevanza perché raccolto prospetticamente e proveniente da uno studio di popolazione e pertanto non viziato da bias di selezione né da valutazioni a posteriori, sebbene sia limitato dal fatto che l’esame endoscopico non sia stato effettuato in tutti i pazienti e che l’analisi sulla base della guarigione endoscopica non sia l’obiettivo dello studio, ma un riscontro successivo, per cui la numerosità campionaria non era stata ricercata su questo specifico outcome.
- Le analisi accessorie dello studio ACCENT II, dimostrano che anche nell’ambito della patologia fistolizzante il trattamento con infliximab determina una marcatissima riduzione degli interventi chirurgici maggiori, che è significativa sia laddove vengano considerati tutti i pazienti randomizzati, sia (all’incirca con eguale magnitudine) considerando solo i pazienti che sono stati randomizzati nello studio sulla base del riscontro di una risposta iniziale. Mentre i pazienti trattati con biologico presentavano un rischio di 2 interventi chirurgici per 100 pazienti per anno, il rischio di coloro che erano stati mantenuti con placebo si attestava tra gli 11 ed i 13 interventi chirurgici per 100 pazienti per anno.
- Anche nello studio Charm, con adalimumab, è stato possibile dimostrare una significativa riduzione del numero di ricoveri per Crohn nei trattati con il farmaco attivo rispetto al placebo: la riduzione relativa del rischio è del 78% a 3 mesi e del 57% all’anno di trattamento rispetto al placebo: la forbice raggiunge la significatività statistica a partire dalla settimana 2 dopo la randomizzazione, all’anno di trattamento il rischio cumulativo di aver subito un ricovero nel gruppo adalimumab si attesta intorno al 7%, mentre quello del gruppo placebo è del 16%. Log-rank test: risk was significantly different (p<0.01)
- At 5 years (red circle), it appears as if ~58% of UC patients (Ferrante) and ~58% of CD patients (Schnitzler) had a sustained clinical response.
- At 5 years (red circle), it appears as if ~58% of UC patients (Ferrante) and ~58% of CD patients (Schnitzler) had a sustained clinical response.
- Dal punto di vista della sostenibilità dei trattamenti con anti-TNF, invece, le osservazioni dello studio ADHERE ( estensione in aperto dello studio CHARM) dimostrano che a 3 anni dall’inizio del trattamento con adalimumab, la remissione di malattia viene mantenuta in 4/5 dei pazienti che l’avevano ottenuta al termine delle 56 settimane dello studio CHARM.
- Al termine dello studio Step-up/Top-down si era osservato 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. Questo dato osservazionale rappresenta la premessa dell’osservazione dello studio di follow-up, perché in quanto tale rappresenta invece unicamente un’osservazione di un dato clinico.