MALATTIE INFIAMMATORIE CRONICHE INTESTINALI: I LIMITI DELLA TERAPIA TRADIZIONALE. QUANDO INIZIARE I FARMACI BIOLOGICI? GENOVA 26 NOVEMBRE 2011 XI CONGRESSO.

Presentazione sul tema: "MALATTIE INFIAMMATORIE CRONICHE INTESTINALI: I LIMITI DELLA TERAPIA TRADIZIONALE. QUANDO INIZIARE I FARMACI BIOLOGICI? GENOVA 26 NOVEMBRE 2011 XI CONGRESSO."— Transcript della presentazione:

1 MALATTIE INFIAMMATORIE CRONICHE INTESTINALI: I LIMITI DELLA TERAPIA TRADIZIONALE. QUANDO INIZIARE I FARMACI BIOLOGICI? GENOVA 26 NOVEMBRE 2011 XI CONGRESSO TRISOCIETARIO LIGURE DI GASTROENTEROLOGIA GIOVANNI RUSSO S.C. GASTROENTEROLOGIA ASL5 LA SPEZIA

2 IBD: GUIDELINES “The second European evidence-based consensus on the diagnosis and management of Crohn’s disease: current management” CONSENSUS ECCO 2010 (Journal of Crohn and Colitis 2010) “European evidence-based Consensus on the management of ulcerative colitis: current management” CONSENSUS ECCO 2008 (Journal of Crohn and Colitis 2008) “The Ital. Society of Gastroenterology (SIGE) and the Ital. Group for the study of Inflammatory Bowel Disease (IG-IBD) Clinical Practice Guide: The use of tumor necrosis factor-alpha antagonist therapy in Inflammatory Bowel Disease” (Digestive and Liver Disease 2010)

3 TERAPIA TRADIZIONALE MESALAZINA STEROIDI AZATIOPRINA (6MP)
CICLOSPORINA METOTREXATE ANTIBIOTICI

4 SHORT AND LONG TERM OUTCOME OF CORTICOSTEROIDS IN CD
100 REFRACTORY REFRACTORY 80 DEPENDENCY 60 RESPONSE 40 20 RESPONSE Munkholm 1994, Faubion 2001, Ho, 2006, Papi 2007 1 year 1 month

5 TROPPI EFFETTI COLLATERALI
STEROIDI: LIMITI TROPPI EFFETTI COLLATERALI (ATTENTI ALL’AUTOPRESCRIZIONE!) Cardiovascolari: ipertensione Dermatologici: Ecchimosi, petecchie, strie rubre, acne Endocrino-metabolici (Soppressione asse ipotalamo-ipofisi-surrene, irsutismo, aspetto cushingoide, impotenza, irregolarità mestruali, ritardo e arresto della crescita nei bambini, diabete, catabolismo proteico, disturbi elettrolitici ritenzione di sodio e acqua, ipokaliemia, ipocalcemia, calciuria) Gastrointestinali; Ulcera peptica, emorragia gastrica Immunitari: Aumentata suscettibilità alle infezioni, ritardata guarigione di ferite Neuropsichici: Iperattività psico-motoria, euforia, insonnia, sindrome depressivo-maniacali, psicosi Oftalmici: Cataratta, glaucoma, cheratiti Osteomuscolari: Osteoporosi, necrosi asettica della testa del femore e dell’omero, miopatia

6 IMMUNOSOPPRESSORI: QUANDO? consensus E.C.C.O. 2010
RECIDIVE SEVERE RECIDIVE FREQUENTI (almeno 2 cicli di steroidi/anno) RECIDIVE RAPIDE (dopo meno di 3 mesi dalla sospensione dello steroide) PROFILASSI POST-OPERATORIA (malattia estesa o fistolizzante) 60-70% dei pazienti mantiene la remissione clinica a 18 mesi Farmaci “lenti”, dai 3 ai 6 mesi per valutare se efficaci o no Tempo di terapia almeno 4 anni; uno stop precoce aumenta il rischio di recidiva Non cambiano la storia della malattia e non riducono gli interventi chirurgici

7 Azathioprine is not altering the natural history of Crohn’s disease
Cosnes J et al Gut 2005

8 Safety azatioprina Effetti avversi 138/333 (41%)
Precoci 86/134 (25.9%) stop terapia 81/86 (94.2%) Tardivi 52/134 (15.7%) stop terapia 38/52 (73.1%) Daperno M et al. Dig Liver Dis 2011 (A)

9 Hospitalisations and surgeries drive costs in Crohn’s Disease (PRE-BIOLOGIC ERA)
Hospitalization 33.7% Diagnostic W/U 1.5% 80% Complications 5.5% Outpatient 2.9% Surgery 46.2% Medications 10.2% Hay JW, et al. J Clin Gastroenterol. 1992; 14:309 9 9

10 Natural history of IBD Risk of stricturing and perforating complications in CD is above 50% over years (peyrin-biroulet Am J Gastroent 2010) The proportion of patients having to undergo surgical resection in CD is around 50% over 10 years (peyrin-biroulet Am J Gastroent 2010) In UC the rate of IPAA is between 10 and 30% in years (hoie 2007 gastroenterology) Increased risk of colon cancer associated with chronic uncontrolled colonic inflammation (rutter gastroenterology 2004)

11 Therapeutic goals in IBD: anti-TNF
Induce rapid response and maintain steroid-free remission Achieve and maintain complete mucosal healing DEEP REMISSION (clinical, biological and endoscopic) Improve quality of life Avoid complications (i.e. hospitalisation and surgery) Prevention of post-op recurrences SAFETY The timing of anti-TNF introduction is a key issue in CD and UC management: change the natural history of IBD? Panaccione, alim therapeut 2008

12 IFX and ADA STUDIES INFLIXIMAB 1999 (CD and UC): ADALIMUMAB 2007 (CD):
TARGAN (chimeric monoclonal antibody…) Nejm 1998 ACCENT1 (luminal disease), Hanauer Lancet 2002 ACCENT 2 (fistulizing disease), Sands Gastroenterology 2002 ACT1/ACT2 (induction and mainten.) Rutgeerts Nejm 2005 STEP-UP/TOP DOWN, Hommes Gastroenterology 2006 TREAT (safety) Lichtenstein Clin Gastroenterol Hepatol 2006 REACH (maintenance) Panaccione Aliment Pharmacol Ther 2007 SONIC (mono/combo) Colombel Nejm 2010 SUCCESS (mucosal healing,UC, ifx) Panaccione, J Crohn Colitis 2011 ADALIMUMAB 2007 (CD): CLASSIC (induction) Hanauer, Gastroenterology 2006 GAIN (induction) Sandborn, Annals of Int Med 2007 CHARM (maintenance) Feagan, Am J Gastroent 2008 ADHERE (maintenance) Panaccione, Aliment Pharm & Therapeut 2010 EXTEND (mucosal healing) Rutgeerts, Gastroenterol 2010 CARE (safety and efficacy) Lofberg, Inflammatory Bowel Disease 2011

13 Anti-TNF: STEP UP STRATEGY
The treatment is progressively increased in case of absence of response to the previous treatment tried Both in CD and UC, 3 steps can be recognised: mesalazine, IS and anti-TNF in mono or combo therapy. (The steroids are only a temporary adjuvant treatment at any step but not representing a step by themself) The main idea behind this strategy is to avoid overtreatment either because the cost, safety or patients-comfort The main risk is undertreatment leading to tissue damage or disability

14 ECCO indications for anti TNF in CD and UC
a) CD :  Treatment of severe, active CD in patients who have not responded despite a full and adequate course of therapy with a corticosteroid and/or an immunosuppressant, or who are intolerant to or have medical contraindications for such therapies Fistulising CD :   Treatment of fistulising, active CD in patients who have not responded despite a full and adequate course of therapy with conventional treatment (including antibiotics, drainage and immunosuppressive therapy)     UC : Treatment of moderately to severely active UC in patients who have had an inadequate response to conventional therapy, including corticosteroids and azathioprine, or who are intolerant to or have medical contraindications for such therapies ECCO guidelines

15 Anti -TNF : TOP DOWN STRATEGY
a combined treatment with IS and anti-TNF is started from the beginning and then a decrease (anti-TNF and/or IS treatment cessation) can be considered if the disease is adequately controlled (D’Haens, lancet 2008) an infliximab-based treatment strategy, especially in AZA-naïve patients with high inflammatory burden at baseline, provides the most benefit in improving therapeutic outcomes (Danese, Al Pharmacol Therapy 2011) The main idea behind the top down approach is to avoid undertreatment mainly because of the potentially dramatic natural history of the disease The main risk is overtreatment with potential increased risk and in some cases unjustified increased cost

16 IG-IBD: EARLY TREATMENT IN CD
Statement 4D Early use of Biologics may improve patient outcomes in active CD. However,a widespread use of a“topdown”approach in all CD patients cannot be recommended. Clinical factors at diagnosis may predict poor outcome in CD and should be taken into account when determining the initial therapeutic approach However,the benefit of early treatment with biologics in this patient subgroup is not proven

17 High risk of “aggressive” disease
Disease location and behaviour Rectal disease Perianal lesions Extensive small bowel disease Severe upper gastro-intestinal disease Severe extraintestinal manifestations (25-40%) Deep ulcers Steroids for first flare High serologic titers (elevated CRP) Worsening factors Smoking Young age at diagnosis (<40) Genetic and serological profile (future?) BEAUGERIE GASTROENTEROLOGY LOLY SCAND J GASTR 2008

18 THE FUTURE IS TOMORROW “Role of genetics in prediction of disease course and response to therapy” Severine Vermeire, Gert Van Assche, Paul Rutgeerts World J Gastroenterol 2010 June 7; 16(21):

19 AND NOW? TAILORED THERAPY !
Optimal current approach is a mix of accelerated step up and targeted top down: in relation to the variable and heterogeneous natural history of IBD, the optimal timing of introduction of anti-TNF should be best discussed with the patients on a case by case basis DIGNASS J Crohn Colitis TRAVIS J Crohn Colitis 2008

20 Optimal timing for anti TNF treatment in IBD: consider global disease burden
Benefit; risk of treatment; patient’s preference Disease severity Patient’s expectation Louis, UEGW 2011

21 CD: “BENIGN” DISEASE The patients with a benign disease representing 40% : this group will never need anti-TNF or even IS; they are patients with focal and supeficial disease and usually later onset munkholm scand j gastroenterol 1995

22 CD: “EVOLVING” DISEASE
The patients with initially mild or moderate disease but evolving progressively towards a severe disease representing a 40% Close follow up can show the development of penetrating lesions, disabling extra-intestinal manifestations or incomplete control of the disease after a first or second course of steroids over the first year. The monitoring of these patients by 1) clinical assessment 2) imaging (endoscopic,RMN,VCE) 3) biomarkers (CRP, calprotectin) may help to detect the evolution and trigger the use of anti-TNF in mono or combo therapy LOUIS UEGW 2011 LOUIS UEGW 2011

23 CD: “BAD” DISEASE This group (20%) is characterised by extensive, badly located or penetrating disease from the start: an anti-TNF, preferably in combination with an IS, should be used very early in the disease course COLOMBEL 2010, NEJM

24 Endoscopic healing reduces the risk of surgery and hospitalisation
ACCENT I Endoscopic healing reduces the risk of surgery and hospitalisation Rutgeerts et al. Gastrointestinal Endoscopy 2006

25 Mucosal Healing in CD at Year 2 Predicts Sustained Clinical Remission
Crohn – IFX – Step-up/Top-down trial follow-up Mucosal Healing in CD at Year 2 Predicts Sustained Clinical Remission 49 patients from SUTD trial underwent colonoscopy at year 2 and were followed-up through year 3 and 4 Vi sono poi le osservazioni relative allo studio di follow-up del Step-up Top-down trial. 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. 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 Baert F, et al. Gastroenterology 2010 25 25

26 Massimizzazione efficacia clinica anti-TNF MC studio SONIC
* * p<0.05 vs placebo Colombel JF, et al. NEJM 2010; 362:

27 MONO OR COMBO ? “The risks of combined immunosuppression should be considered, especially in children, young adults or the elderly”. D’Haens, Am J Gastroenterol 2011

28 UC: Predictive Factors of Colectomy
Colectomy Adjusted Hazard Ratio (95% CI) P Value Steroid-dependency 1.84 (1.14–2.97) 0.01 Baseline CRP ≥2 mg/dL 1.73 (1.04–2.88) 0.04 High disease severity (Mayo 10 to 12) 1.84 (1.15–2.94) Moderate to severe UC with duration ≤3 years 0.36 (0.23–0.57) <0.001 Sandborn Gastroenterology. 2009 28 28

29 UC: anti -TNF therapy Effective in steroid-dependent or refractory disease Effective in I.S. naive or refractory In patients with acute severe/fulminant colitis refractory to steroids ev an anti TNF treatment can be proposed from the start Patients with chronic activity of the disease (40-50%) has been associated with a strong impairment of the quality of life and a risk of colectomy and colon cancer; in this case a combo-therapy with anti-TNF and IS should preferably be introduced and decrease the risk of cancer and surgery (mucosal healing) PANACCIONE, J CROHN COLITIS 2011 Rutgeerts 2005, N Engl J med Sandborn 2009 Gastroenterology Panaccione 2011 J crohn and colitis

30 Massimizzazione efficacia clinica anti-TNF RCU studio SUCCESS
* * p<0.05 vs placebo Panaccione R et al. J Crohns Colitis 2011

31 Surgery requirements according to mucosal healing status
Crohn’s disease Ulcerative colitis Pts with MH at 1 year Pts with MH at 1 year Proportion of CD Patients Not Resected Proportion of UC Patients Not Colectomised P=0.02 P=0.10 Pts without MH at 1 year Pts without MH at 1 year Time in Years After 1-Year Visit Time in Years After 1-Year Visit Frøslie KF, et al. Gastroenterology. 2007;133(2): 31 31

32 Summary Persistence of mucosal lesions bears a bad prognosis.
It is possible to achieve and maintain mucosal healing using anti-TNF therapy. Mucosal healing prolongs clinical remission. Mucosal healing reduces complications, hospitalizations and surgery requirements. Mucosal healing may reduce the risk of cancer Preliminary data suggest that anti-TNF treatment may impact the natural history of IBD and increase the chance for the patient to have a normal life louis UEGW 2011

33 CAUTO OTTIMISMO

34 STOP FINE

35 G.L.I.B.D IBD UNIT

36 CONSIDERAZIONI PERSONALI FINALI
paziente sotto i 40 anni malattia clinicamente severa con conseguente bassa qualità di vita gli esami ematici evidenziano importante anemia e/o netto aumento della PCR la colonscopia mi rivela importanti lesioni endoscopiche la RM mi testimonia un importante coinvolgimento ileale il paziente (ed i genitori) sono opportunamente informati con un corretto screening… PRIMA SI INIZIA CON IL BIOLOGICO MEGLIO E’

37 Cosa fare prima di un trattamento con anti-tnf (linee guida Ig-IBD)
Accurata storia clinica e familiare del paziente Terapia biologica controindicata in corso di infezione Screening per la tubercolosi, HBV, HIV, VZV Escludere ascessi addominali e perianali Vaccinazione per HBV, Influenza (consigliata ma non obbligatoria), Pneumococco (negli anziani), Varicella (? ) Consigliati gli “screening” convenzionali per le neoplasie in rapporto ad età e sesso Anti-TNF controindicato in pazienti con neoplasie Anti-TNF controindicato in pazienti con NYHA III-IV Se storia di neoplasie , discuterne caso per caso con l’oncologo Prudenza all’uso concomitante di biologici ed immunosoppressori nei < 40 Prudenza nei pazienti > 65 Gravidanza

38 GRADES OF RECOMMENDATION ECCO
CD UC A (Systematic review with homogeneity of randomised controlled) 18% 20% B (Validating cohort study with good reference standards) 25% 24% C (Case–control study, poor or non-independent reference standard) D(Expert opinion without explicit critical appraisal) 37% 32%

39 GRADES OF RECOMMENDATION IG-IBD
A (Systematic review with homogeneity of randomised controlled) 12% B (Validating cohort study with good reference standards) 29% C (Case–control study, poor or non-independent reference standard) 18% D (Expert opinion without explicit critical appraisal) 41%

40 STEROIDI: LIMITI STEROIDO-RESISTENZA (50-60% A UN ANNO) 1) In caso di uso di steroidi orali si definisce una malattia refrattaria agli steroidi quando i pazienti presentano i sintomi di una malattia attiva nonostante appropriate dosi di prednisone (0,75-1 mg/kg/die) per un periodo di 2-3 settimane. 2) In caso di uso di steroidi per via endovenosa quando i pazienti hanno malattia attiva nonostante dosi appropriate di metilprednisolone (1 mg/kg/die) per un periodo di una settimana. STEROIDO-DIPENDENZA (30-40% A UN ANNO) 1) Un paziente necessita di due o piu’ cicli di steroidi entro i 12 mesi 2) un paziente non riesce a sospendere la terapia con steroidi entro 3 mesi dall'inizio della terapia senza incorrere in una recidiva clinica; 3) un paziente ha una ripresa dei sintomi classificabile come riacutizzazione entro i 3 mesi dal termine della terapia con steroidi.

41 UEGW 2011 PRESENTATIONS Noninvasive diagnostic tools for monitoring IBD (IRVING,UK) Timing of introduction of biologic therapies in CD and UC (LOUIS, BELGIUM) How to evaluate and follow anti-TNF treated patients (VAN ASSCHE, BELGIUM) Role of therapeutic drug monitoring (ALLEZ, FRANCE) Perioperative management of CD: how to prepare patients for surgery (FORBES, UK) Perioperative management of CD: postoperative prevention of recurrence (REGUEIRO, USA) Medical treatment of severe colitis (LAHARIE, FRANCE)

42 I COSTI INFLIXIMAB 300mg/2 mesi= COSTO/ANNO 10000 €
ADALIMUMAB 40 mg/2 sett= COSTO/anno: € Un giorno di ricovero in ospedale: in media 500 €/die Un intervento chirurgico VLC sull’addome= 2000/5000 €

43 CD: Evidence based Anti-TNF efficacy
Anti TNF treatment have been prove effective both as an induction and maintenance therapy in : 1) Active luminal disease 2) Peri-anal fistuling disease 3) Steroid-naive, dependent or refractory disease 4) Immunosoppressant-naive or refractory disease Oussalah, Curr Drug Targets 2010

44 Thiopurines could be added in naïve patients
Induction and maintenance of remission in moderate-to-severe steroid-refractory or dependent CD IG-IBD Statement 4A Anti-TNF agents are a valuable option in moderate-to-severe steroid- refractory or dependent CD Thiopurines could be added in naïve patients Adalimumab can be used as a second line treatment in patients with primary failures to infliximab or with loss of response or intolerance to infliximab

45 Maintenance of remission in luminal CD
IG-IBD Statement 4B Anti-TNF agents are effective for maintenance of remission up to 1 year in patients with clinical response to induction therapy Anti-TNF agents should be the treatment of choice for patients who have failed maintenance strategies with immuno- suppressants

46 Management of perianal complex fistulas
IG-IBD Statement 5D “Cone-like” fistulectomy of each fistula tract should firstly be performed with sparing of sphincteric structures Seton placement should be recommended,the timing of removal depending on subsequent therapy. Anti-TNF agents should be used as the first choice of medical therapy for complex perianal CD Combination with surgical therapy is recommended despite a lack of clinical trials Antibiotics and/or azathioprine/6-mercaptopurines should be used as a second line medical treatment,despite a lack of clinical trials

47 Induction and maintenance of response/remission in moderate-to-severe steroid-refractory or steroid-dependent UC IG-IBD Statement 6A-B Infliximab induction regimen can be used in patients with moderate-to-severe UC who are refractory to systemic corticosteroids and in corticosteroid-dependent patients who are intolerant/refractory to thiopurines.One year scheduled treatment with Infliximab can be used in patients who have responded to infliximab induction. In patients who are thiopurine-naïve, maintenance therapy with thiopurines alone is a valuable option.The duration of the therapy over 1 year should be carefully evaluated on a case-by-case basis Maintenance therapy with infliximab that achieves only response should be carefully evaluated in the face of a colectomy

48 Induction and maintenance of response/remission in severe steroids refractory UC
IG-IBD Statement 7A Infliximab reduces colectomy rate within 3 months in steroid-refractory severe UC A colectomy is recommended if there is no improvement within 5days[EL5,RG D]. Infliximab should be avoided in patients with a complicated disease Reinfusions seem more effective than one single infusion to prevent early colectomy, but there is insufficient evidence to provide recommendations on the ideal dosing schedule.Antibiotic prophylaxis against opportunistic infections is suggested

49 “INTERAZIONI” nell’outcome delle M.I.C.I.
Fenotipo Decorso Risultato Fattori genotipici TERAPIA Fattori demografici Fattori psicosociali Fattori ambientali Wolters F, et al SJG 2006 La malattia di Crohn e la rettocolite ulcerosa costituiscono un gruppo di malattie infiammatorie croniche del tratto gastrointestinale ad origine non ancora ben conosciuta, comunemente definite come malattie infiammatorie croniche intestinali. I primi segni di queste malattie spesso compaiono in età giovanile ed il loro decorso può essere estremamente debilitante. Sulla base di queste premesse è chiaro come cercare di migliorare il più possibile l’outcome di queste malattie sia una sfida di fondamentale importanza per i medici dedicati. In maniera schematica, si può oggi ipotizzare che l’outcome delle malattie infiammatorie croniche intestinale dipenda da un continuo interplay tra fattori genotipici, ambientali, demografici, psicosociali e, non meno importante, medico-sanitari. In definitiva, lo stato di salute dell’individuo con malattia infiammatoria cronica intestinale dovrebbe essere considerato come risultato dell’interazione continua di queste variabili.