MALATTIE INFIAMMATORIE CRONICHE INTESTINALIMALATTIE INFIAMMATORIE CRONICHE INTESTINALI: : I LIMITI DELLA TERAPIA TRADIZIONALE. I LIMITI DELLA TERAPIA TRADIZIONALE.

QUANDO INIZIARE I FARMACI BIOLOGICI?QUANDO INIZIARE I FARMACI BIOLOGICI?

GENOVA 26 NOVEMBRE 2011GENOVA 26 NOVEMBRE 2011 XI CONGRESSO TRISOCIETARIOXI CONGRESSO TRISOCIETARIO

LIGURE DI GASTROENTEROLOGIALIGURE DI GASTROENTEROLOGIA

GIOVANNI RUSSOGIOVANNI RUSSO S.C. GASTROENTEROLOGIAS.C. GASTROENTEROLOGIA ASL5 LA SPEZIAASL5 LA SPEZIA

“European evidence-based Consensus on the management of ulcerative colitis: current management”CONSENSUS ECCO 2008 (Journal of Crohn and Colitis 2008)

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)

“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)

TERAPIA TRADIZIONALETERAPIA TRADIZIONALE

MESALAZINAMESALAZINA STEROIDISTEROIDI AZATIOPRINA (6MP)AZATIOPRINA (6MP) CICLOSPORINACICLOSPORINA METOTREXATEMETOTREXATE ANTIBIOTICIANTIBIOTICI

100

20

40

60

80

0

1 month 1 year

RESPONSE

REFRACTORY

REFRAC

TORY

RES

PO

NS

E

DEPENDENCY

Munkholm 1994, Faubion 2001, Ho, 2006, Papi 2007

TROPPI EFFETTI COLLATERALI(ATTENTI ALL’AUTOPRESCRIZIONE!)

STEROIDI: LIMITI

CardiovascolariCardiovascolari: ipertensione: ipertensioneDermatologiciDermatologici: Ecchimosi, petecchie, strie rubre, acne: Ecchimosi, petecchie, strie rubre, acneEndocrino-metabolicEndocrino-metabolici (Soppressione asse ipotalamo-i (Soppressione asse ipotalamo-ipofisi-surrene, irsutismo, aspetto cushingoide, ipofisi-surrene, irsutismo, aspetto cushingoide, impotenza, irregolarità mestruali, ritardo e arresto della impotenza, irregolarità mestruali, ritardo e arresto della crescita nei bambini, diabete, catabolismo proteico, crescita nei bambini, diabete, catabolismo proteico, disturbi elettrolitici ritenzione di sodio e acqua, disturbi elettrolitici ritenzione di sodio e acqua, ipokaliemia, ipocalcemia, calciuria)ipokaliemia, ipocalcemia, calciuria)GastrointestinaliGastrointestinali; Ulcera peptica, emorragia gastrica; Ulcera peptica, emorragia gastricaImmunitariImmunitari: Aumentata suscettibilità alle infezioni, : Aumentata suscettibilità alle infezioni, ritardata guarigione di feriteritardata guarigione di feriteNeuropsichiciNeuropsichici: Iperattività psico-motoria, euforia, : Iperattività psico-motoria, euforia, insonnia, sindrome depressivo-maniacali, psicosiinsonnia, sindrome depressivo-maniacali, psicosiOftalmiciOftalmici: Cataratta, glaucoma, cheratiti: Cataratta, glaucoma, cheratitiOsteomuscolariOsteomuscolari: Osteoporosi, necrosi asettica della : Osteoporosi, necrosi asettica della testa del femore e delltesta del femore e dell’’omero, miopatiaomero, miopatia

IMMUNOSOPPRESSORI: QUANDO?IMMUNOSOPPRESSORI: QUANDO?consensus E.C.C.O. 2010consensus E.C.C.O. 2010

1)1) RECIDIVE SEVERERECIDIVE SEVERE

2)2) RECIDIVE FREQUENTI (almeno 2 cicli di steroidi/anno)RECIDIVE FREQUENTI (almeno 2 cicli di steroidi/anno)

3)3) RECIDIVE RAPIDE (dopo meno di 3 mesi dalla sospensione RECIDIVE RAPIDE (dopo meno di 3 mesi dalla sospensione dello steroide)dello steroide)

4)4) PROFILASSI POST-OPERATORIA (malattia estesa o PROFILASSI POST-OPERATORIA (malattia estesa o fistolizzante)fistolizzante)

60-70% dei pazienti mantiene la remissione clinica a 18 mesi 60-70% dei pazienti mantiene la remissione clinica a 18 mesi Farmaci “lenti”, dai 3 ai 6 mesi per valutare se efficaci o noFarmaci “lenti”, dai 3 ai 6 mesi per valutare se efficaci o no

Tempo di terapia almeno 4 anni; uno stop precoce aumenta il Tempo di terapia almeno 4 anni; uno stop precoce aumenta il rischio di recidivarischio di recidiva

Non cambiano la storia della malattia e Non cambiano la storia della malattia e non riducono gli interventi chirurgicinon riducono gli interventi chirurgici

Azathioprine is not altering the natural Azathioprine is not altering the natural history of Crohn’s diseasehistory of Crohn’s disease

Cosnes J et al Gut 2005

0

10

20

30

40

50

60

1978-1982 1983-1987 1988-1992 1993-1997 1998-2002

Immosuppressant Use P<0.001

Resection p=0.5

Stoma p=0.7

Safety azatioprinaEffetti 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)

Hospitalisations and surgeries drive Hospitalisations and surgeries drive costs in Crohn’s Disease (PRE-costs in Crohn’s Disease (PRE-

BIOLOGIC ERA)BIOLOGIC ERA)

Hay JW, et al. J Clin Gastroenterol. 1992; 14:309

80%

Diagnostic W/U1.5%

Hospitalization33.7%

Complications5.5%

Outpatient2.9%

Medications10.2%

Surgery46.2%

Natural history of IBDNatural history of IBD Risk of stricturing and perforating complications Risk of stricturing and perforating complications

in CD is above 50% over 10 - 20 yearsin CD is above 50% over 10 - 20 years (peyrin-(peyrin-biroulet Am J Gastroent 2010)biroulet Am J Gastroent 2010)

The proportion of patients having to undergo The proportion of patients having to undergo surgical resection in CD is around 50% over 10 surgical resection in CD is around 50% over 10 yearsyears ((peyrin-birouletpeyrin-biroulet Am J Gastroent 2010)Am J Gastroent 2010)

In UC the rate of IPAA is between 10 and 30% in In UC the rate of IPAA is between 10 and 30% in 10 - 20 years10 - 20 years (hoie 2007 gastroenterology)(hoie 2007 gastroenterology)

Increased risk of colon cancer associated with Increased risk of colon cancer associated with chronic uncontrolled colonic inflammationchronic uncontrolled colonic inflammation (rutter(rutter gastroenterology 2004)gastroenterology 2004)

Induce rapid response and maintain steroid-free Induce rapid response and maintain steroid-free remission remission

Achieve and maintain complete Achieve and maintain complete mucosal healingmucosal healing DEEP REMISSIONDEEP REMISSION (clinical, biological and endoscopic)(clinical, biological and endoscopic) Improve quality of life Improve quality of life Avoid complications (i.e. hospitalisation and surgery)Avoid complications (i.e. hospitalisation and surgery) Prevention of post-op recurrencesPrevention of post-op recurrences SAFETYSAFETY

Therapeutic goals in IBD: anti-TNFTherapeutic goals in IBD: anti-TNF

The timing of anti-TNF introduction is a The timing of anti-TNF introduction is a

key issue in CD and UC management: key issue in CD and UC management:

change the natural history of IBD?change the natural history of IBD? Panaccione, alim therapeut 2008Panaccione, alim therapeut 2008

IFX and ADA STUDIESIFX and ADA STUDIESINFLIXIMAB 1999 (CD and UC):INFLIXIMAB 1999 (CD and UC):TARGANTARGAN (chimeric monoclonal antibody…) (chimeric monoclonal antibody…) Nejm 1998Nejm 1998ACCENT1ACCENT1 (luminal disease), Hanauer (luminal disease), Hanauer Lancet 2002Lancet 2002ACCENT 2ACCENT 2 (fistulizing disease), Sands (fistulizing disease), Sands GastroenterologyGastroenterology 20022002ACT1/ACT2ACT1/ACT2 (induction and mainten.) Rutgeerts (induction and mainten.) Rutgeerts NejmNejm 20052005 STEP-UP/TOP DOWNSTEP-UP/TOP DOWN, Hommes , Hommes Gastroenterology 2006Gastroenterology 2006TREATTREAT (safety) Lichtenstein (safety) Lichtenstein Clin Gastroenterol HepatolClin Gastroenterol Hepatol 2006 2006 REACHREACH (maintenance) Panaccione (maintenance) Panaccione Aliment Pharmacol TherAliment Pharmacol Ther 20072007SONICSONIC (mono/combo) Colombel (mono/combo) Colombel NejmNejm 20102010SUCCESSSUCCESS (mucosal healing,UC, ifx) Panaccione, (mucosal healing,UC, ifx) Panaccione, J Crohn ColitisJ Crohn Colitis 20112011

ADALIMUMAB 2007 (CD):ADALIMUMAB 2007 (CD): CLASSICCLASSIC (induction) Hanauer, (induction) Hanauer, GastroenterologyGastroenterology 20062006GAINGAIN (induction) Sandborn, (induction) Sandborn, Annals of Int MedAnnals of Int Med 20072007CHARMCHARM (maintenance) Feagan, (maintenance) Feagan, Am J GastroentAm J Gastroent 20082008ADHEREADHERE (maintenance) Panaccione, (maintenance) Panaccione, Aliment Pharm & TherapeutAliment Pharm & Therapeut 20102010EXTENDEXTEND (mucosal healing) Rutgeerts, (mucosal healing) Rutgeerts, GastroenterolGastroenterol 20102010CARECARE (safety and efficacy) Lofberg, (safety and efficacy) Lofberg, Inflammatory Bowel DiseaseInflammatory Bowel Disease 20112011

Anti-TNF: STEP UP Anti-TNF: STEP UP STRATEGYSTRATEGY

The treatment is progressively increased in case of absence The treatment is progressively increased in case of absence

of response to the previous treatment triedof response to the previous treatment tried

Both in CD and UC, 3 steps can be recognised: mesalazine, Both in CD and UC, 3 steps can be recognised: mesalazine,

IS and anti-TNF in mono or combo therapy. IS and anti-TNF in mono or combo therapy. (The steroids are (The steroids are

only a temporary adjuvant treatment at any step but not only a temporary adjuvant treatment at any step but not

representing a step by themself)representing a step by themself)

The main idea behind this strategy is to avoid overtreatment The main idea behind this strategy is to avoid overtreatment

either because the cost, safety or patients-comforteither because the cost, safety or patients-comfort

The main risk is undertreatment leading to tissue damage or The main risk is undertreatment leading to tissue damage or

disabilitydisability

ECCO indications for anti TNF in CD and UCECCO indications for anti TNF in CD and UC

aa)) CDCD :  Treatment of severe, active CD in patients who have :  Treatment of severe, active CD in patients who have not respondednot responded despite a full and adequate course of despite a full and adequate course of therapy with a corticosteroid and/or an therapy with a corticosteroid and/or an immunosuppressant, or who are immunosuppressant, or who are intolerantintolerant to or have to or have medical medical contraindicationscontraindications for such therapies for such therapies

b)b) Fistulising CDFistulising CD : :   Treatment of fistulising, active CD in    Treatment of fistulising, active CD in patients who have patients who have not respondednot responded despite a full and despite a full and adequate course of therapy with conventional treatment adequate course of therapy with conventional treatment (including antibiotics, drainage and immunosuppressive (including antibiotics, drainage and immunosuppressive therapy)therapy)       

c)c) UCUC : : Treatment of moderately to severely active UC in Treatment of moderately to severely active UC in patients who have had an patients who have had an inadequate responseinadequate response to to conventional therapy, including corticosteroids and conventional therapy, including corticosteroids and azathioprine, or azathioprine, or who are intolerantwho are intolerant to or have medical to or have medical contraindicationscontraindications for such therapies for such therapies

ECCO guidelines 2008-2010ECCO guidelines 2008-2010

Anti -TNF : TOP DOWN STRATEGYAnti -TNF : TOP DOWN STRATEGY a combined treatment with IS and anti-TNF is started from the a combined treatment with IS and anti-TNF is started from the

beginning and then a decrease (anti-TNF and/or IS treatment beginning and then a decrease (anti-TNF and/or IS treatment

cessation) can be considered if the disease is adequately cessation) can be considered if the disease is adequately

controlled controlled (D(D’’Haens, lancet 2008)Haens, lancet 2008)

an infliximab-based treatment strategy, especially in AZA-naïve an infliximab-based treatment strategy, especially in AZA-naïve

patients with high inflammatory burden at baseline, provides the patients with high inflammatory burden at baseline, provides the

most benefit in improving therapeutic outcomes most benefit in improving therapeutic outcomes

((Danese, Al Pharmacol Therapy 2011)Danese, Al Pharmacol Therapy 2011)

The main idea behind the top down approach is to avoid The main idea behind the top down approach is to avoid

undertreatment mainly because of the potentially dramatic natural undertreatment mainly because of the potentially dramatic natural

history of the diseasehistory of the disease

The main risk is overtreatment with potential increased risk and in The main risk is overtreatment with potential increased risk and in

some cases unjustified increased costsome cases unjustified increased cost

IG-IBD: EARLY TREATMENT IN CDIG-IBD: EARLY TREATMENT IN CD

Statement 4DStatement 4D Early use of Biologics Early use of Biologics maymay improve patient improve patient

outcomes in active CD.outcomes in active CD.

HoweverHowever,a widespread use of ,a widespread use of a“topdown”approach in all CD patients cannot a“topdown”approach in all CD patients cannot

be recommended.be recommended.

Clinical factors at diagnosisClinical factors at diagnosis maymay predict poorpredict poor outcomeoutcome in CD and should be taken into account in CD and should be taken into account

when determining the initial therapeutic when determining the initial therapeutic approachapproach

HoweverHowever,the benefit of early treatment with ,the benefit of early treatment with biologics in this patient subgroup is not proven biologics in this patient subgroup is not proven

High risk of High risk of ““aggressiveaggressive”” disease disease

Disease location and behaviourDisease location and behaviourRectal diseaseRectal diseasePerianal lesionsPerianal lesionsExtensive small bowel diseaseExtensive small bowel diseaseSevere upper gastro-intestinal diseaseSevere upper gastro-intestinal diseaseSevere extraintestinal manifestations (25-40%)Severe extraintestinal manifestations (25-40%)Deep ulcersDeep ulcers

Steroids for first flareSteroids for first flare High serologic titers (elevated CRP)High serologic titers (elevated CRP)

Worsening factorsWorsening factorsSmokingSmokingYoung age at diagnosis (<40)Young age at diagnosis (<40)Genetic and serological profile (future?)Genetic and serological profile (future?)

BEAUGERIE GASTROENTEROLOGY 2006 LOLY SCAND J GASTR 2008BEAUGERIE GASTROENTEROLOGY 2006 LOLY SCAND J GASTR 2008

THE FUTURE IS TOMORROWTHE 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): 2609-2615

AND NOW? AND NOW?

Optimal current approach is a Optimal current approach is a mixmix of of accelerated step upaccelerated step up and and targeted toptargeted top downdown: in relation to the variable and : in relation to the variable and

heterogeneous natural history of IBD, the heterogeneous natural history of IBD, the optimal timing of introduction of anti-TNF optimal timing of introduction of anti-TNF should be best discussed with the patients should be best discussed with the patients

on a case by case basis on a case by case basis

DIGNASS J Crohn Colitis 2010 TRAVIS J Crohn Colitis 2008DIGNASS J Crohn Colitis 2010 TRAVIS J Crohn Colitis 2008

TAILORED THERAPY !TAILORED THERAPY !

Optimal timing for anti TNF treatment in IBD: Optimal timing for anti TNF treatment in IBD: consider global disease burdenconsider global disease burden

Benefit; risk of treatment; patientBenefit; risk of treatment; patient’’s preferences preference

Disease severity Patient’s expectation

Louis, UEGW 2011

CD: CD: ““BENIGNBENIGN”” DISEASE DISEASE

The patients with a benign disease The patients with a benign disease representing 40% : this group will representing 40% : this group will

never need anti-TNF or even IS; they never need anti-TNF or even IS; they are patients with focal and supeficial are patients with focal and supeficial

disease and usually later onsetdisease and usually later onset

munkholm scand j gastroenterol 1995munkholm scand j gastroenterol 1995

CD: CD: ““EVOLVINGEVOLVING”” DISEASE DISEASE The patients with initially mild or moderate disease but evolving progressively towards a severe disease representing a 40%The patients with initially mild or moderate disease but evolving progressively towards a severe disease representing a 40%

Close follow upClose 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. 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 The monitoring of these patients by

1) 1) clinical assessment clinical assessment

2) 2) imaging (endoscopic,RMN,VCE)imaging (endoscopic,RMN,VCE)

3)3) biomarkers (CRP, calprotectin) biomarkers (CRP, calprotectin)

may help to detect the evolution and may help to detect the evolution and triggertrigger the use of anti-TNF in mono or combo therapy the use of anti-TNF in mono or combo therapy LOUIS UEGW 2011LOUIS UEGW 2011

LOUIS UEGW 2011LOUIS UEGW 2011

CD: CD: ““BADBAD”” DISEASE DISEASE

This group (20%) is characterised by This group (20%) is characterised by extensive, badly located or penetrating extensive, badly located or penetrating

disease from the start: an anti-TNF, disease from the start: an anti-TNF, preferably in combination with an IS, preferably in combination with an IS,

should be used very early in the disease should be used very early in the disease coursecourse

COLOMBEL 2010, NEJMCOLOMBEL 2010, NEJM

Endoscopic healing reduces the risk of Endoscopic healing reduces the risk of surgery and hospitalisationsurgery and hospitalisation

Rutgeerts et al. Gastrointestinal Endoscopy 2006

ACCENT I

Baert F, et al. Gastroenterology 2010

49 patients from SUTD trial underwent colonoscopy at year 2

and were followed-up through year 3 and 4

Mucosal Healing in CD at Year 2 Predicts Mucosal Healing in CD at Year 2 Predicts Sustained Clinical RemissionSustained Clinical Remission

Crohn – IFX – Step-up/Top-down trial follow-up

Massimizzazione efficacia clinica anti-TNF

MC studio SONIC

Colombel JF, et al. NEJM 2010; 362:1383-95

30,6%

54,7%

62,7%

44,4%

66,0%72,2%

56,8%

74,1%78,7%

0%

25%

50%

75%

100%

CS-free REMISSION w26 Clinical REMISSION w50 D100 RESPONSE w50

Perc

ent

of pati

ents

AZA IFX IFX+AZA

*

*

**

* p<0.05 vs placebo

MONO OR COMBO ?MONO OR COMBO ?

““The risks of combined immunosuppression The risks of combined immunosuppression should be considered, especially in should be considered, especially in

children, young adults or the elderly”. children, young adults or the elderly”.

D’Haens, Am J Gastroenterol 2011D’Haens, Am J Gastroenterol 2011

UC: Predictive Factors of ColectomyUC: Predictive Factors of Colectomy

Predictive FactorPredictive Factor Colectomy Colectomy Adjusted Hazard Adjusted Hazard

Ratio (95% CI)Ratio (95% CI)

PP Value Value

Steroid-dependencySteroid-dependency 1.84 (1.14–2.97)1.84 (1.14–2.97) 0.010.01

Baseline CRP ≥2 Baseline CRP ≥2 mg/dLmg/dL

1.73 (1.04–2.88)1.73 (1.04–2.88) 0.040.04

High disease severity High disease severity (Mayo 10 to 12)(Mayo 10 to 12)

1.84 (1.15–2.94)1.84 (1.15–2.94) 0.010.01

Moderate to severe Moderate to severe UC with duration ≤3 UC with duration ≤3 yearsyears

0.36 (0.23–0.57)0.36 (0.23–0.57) <0.001<0.001

Sandborn Gastroenterology. 2009

UC: anti -TNF therapyUC: anti -TNF therapy

Effective in steroid-dependent or refractory diseaseEffective in steroid-dependent or refractory disease

Effective in I.S. naive or refractoryEffective in I.S. naive or refractory

In patients with In patients with acute severe/fulminant colitis refractory to steroids evacute severe/fulminant colitis refractory to steroids ev an an anti TNF treatment can be proposed from the startanti TNF treatment can be proposed from the start

Patients with Patients with chronic activity of the disease (40-50%)chronic activity of the disease (40-50%) has been has been associated with a strong impairment of the quality of life and a risk of 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-colectomy and colon cancer; in this case a combo-therapy with anti-TNF and IS should preferably be introduced and decrease the risk of TNF and IS should preferably be introduced and decrease the risk of cancer and surgery (mucosal healing)cancer and surgery (mucosal healing)

PANACCIONE, J CROHN COLITIS 2011PANACCIONE, J CROHN COLITIS 2011

Rutgeerts 2005, N Engl J med Rutgeerts 2005, N Engl J med Sandborn 2009 GastroenterologySandborn 2009 Gastroenterology Panaccione 2011 J crohn and colitisPanaccione 2011 J crohn and colitis

Massimizzazione efficacia clinica anti-TNFRCU studio SUCCESS

Panaccione R et al. J Crohns Colitis 2011

*

**

*

*

* p<0.05 vs placebo

Surgery requirements according to Surgery requirements according to mucosal healing statusmucosal healing status

Frøslie KF, et al. Gastroenterology. 2007;133(2):412-422.

Ulcerative colitisCrohn’s disease

Pts with MH at 1 year

Pts without MH at 1 year

P=0.10P=0.02

Pts with MH at 1 year

Pts without MH at 1 year

Time in Years After 1-Year Visit

Pro

po

rtio

n o

f C

D P

ati

en

tsN

ot

Res

ecte

d

Pro

po

rtio

n o

f U

C P

ati

en

tsN

ot

Co

lect

om

ised

Time in Years After 1-Year Visit

SummarySummary Persistence of mucosal lesions bears a bad Persistence of mucosal lesions bears a bad

prognosis.prognosis. It is possible to achieve and maintain It is possible to achieve and maintain

mucosal healing using anti-TNF therapy.mucosal healing using anti-TNF therapy. Mucosal healing prolongs clinical remission.Mucosal healing prolongs clinical remission. Mucosal healing reduces complications, Mucosal healing reduces complications,

hospitalizations and surgery requirements. hospitalizations and surgery requirements. Mucosal healing may reduce the risk of Mucosal healing may reduce the risk of

cancercancer Preliminary data suggest that anti-TNF treatment Preliminary data suggest that anti-TNF treatment

may impact the natural history of IBD and increase may impact the natural history of IBD and increase the chance for the patient to have a normal life the chance for the patient to have a normal life

louis UEGW 2011louis UEGW 2011

CAUTO OTTIMISMO CAUTO OTTIMISMO

STOPSTOP

FINEFINE

G.L.I.B.D

IBD UNIT

CONSIDERAZIONI PERSONALI FINALICONSIDERAZIONI PERSONALI FINALI

paziente sotto i 40 annipaziente sotto i 40 anni malattia clinicamente severa con conseguente malattia clinicamente severa con conseguente

bassa qualità di vitabassa qualità di vita gli esami ematici evidenziano importante anemia gli esami ematici evidenziano importante anemia

e/o netto aumento della PCRe/o netto aumento della PCR la colonscopia mi rivela importanti lesioni la colonscopia mi rivela importanti lesioni

endoscopicheendoscopiche la RM mi testimonia un importante la RM mi testimonia un importante

coinvolgimento ilealecoinvolgimento ileale il paziente (ed i genitori) sono opportunamente il paziente (ed i genitori) sono opportunamente

informati con un corretto screening…informati con un corretto screening…

PRIMA SI INIZIA CON IL BIOLOGICO MEGLIO E’PRIMA SI INIZIA CON IL BIOLOGICO MEGLIO E’

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

Cosa fare prima di un trattamento con anti-tnfCosa fare prima di un trattamento con anti-tnf(linee guida Ig-IBD)(linee guida Ig-IBD)

GRADES OF RECOMMENDATION ECCOGRADES OF RECOMMENDATION ECCO

CDCD UCUC

AA ( (Systematic review with homogeneity of randomised controlled)

18%18% 20%20%

B B ((Validating cohort study with good reference standards)

25%25% 24%24%

CC ((Case–control study, poor or non-independent

reference standard)

20%20% 24%24%

D(D(Expert opinion without explicit critical

appraisal)

37%37% 32%32%

GRADES OF RECOMMENDATION IG-IBDGRADES OF RECOMMENDATION IG-IBD

A (A (Systematic review with homogeneity of randomised controlled)

12%12%

B (B (Validating cohort study with good reference standards)

29%29%

C (C (Case–control study, poor or non-independent reference standard)

18%18%

D (D (Expert opinion without explicit critical appraisal)

41%41%

STEROIDI: LIMITISTEROIDI: LIMITISTEROIDO-RESISTENZA (50-60% A UN ANNO)STEROIDO-RESISTENZA (50-60% A UN ANNO) 1) In caso di uso di steroidi orali si definisce una 1) In caso di uso di steroidi orali si definisce una

malattia refrattaria agli steroidi quando i pazienti malattia refrattaria agli steroidi quando i pazienti presentano i sintomi di una malattia attiva nonostante presentano i sintomi di una malattia attiva nonostante appropriate dosi di prednisone (0,75-1 mg/kg/die) per un appropriate dosi di prednisone (0,75-1 mg/kg/die) per un periodo di 2-3 settimane.periodo di 2-3 settimane.

2) In caso di uso di steroidi per via endovenosa quando i 2) In caso di uso di steroidi per via endovenosa quando i pazienti hanno malattia attiva nonostante dosi pazienti hanno malattia attiva nonostante dosi appropriate di metilprednisolone (1 mg/kg/die) per un appropriate di metilprednisolone (1 mg/kg/die) per un periodo di una settimana.periodo di una settimana.

STEROIDO-DIPENDENZA (30-40% A UN ANNO)STEROIDO-DIPENDENZA (30-40% A UN ANNO) 1) Un paziente necessita di due o piu’ cicli di steroidi 1) Un paziente necessita di due o piu’ cicli di steroidi

entro i 12 mesi entro i 12 mesi 2) un paziente non riesce a sospendere la terapia con 2) un paziente non riesce a sospendere la terapia con

steroidi entro 3 mesi dall'inizio della terapia senza steroidi entro 3 mesi dall'inizio della terapia senza incorrere in una recidiva clinica; incorrere in una recidiva clinica;

3) un paziente ha una ripresa dei sintomi classificabile 3) un paziente ha una ripresa dei sintomi classificabile come riacutizzazione entro i 3 mesi dal termine della come riacutizzazione entro i 3 mesi dal termine della terapia con steroidi.terapia con steroidi.

UEGW 2011 PRESENTATIONSUEGW 2011 PRESENTATIONS

Noninvasive diagnostic tools for monitoring IBD Noninvasive diagnostic tools for monitoring IBD (IRVING,UK)(IRVING,UK)

Timing of introduction of biologic therapies in CD and UC Timing of introduction of biologic therapies in CD and UC (LOUIS, BELGIUM)(LOUIS, BELGIUM)

How to evaluate and follow anti-TNF treated patients How to evaluate and follow anti-TNF treated patients (VAN ASSCHE, BELGIUM)(VAN ASSCHE, BELGIUM)

Role of therapeutic drug monitoring (ALLEZ, FRANCE)Role of therapeutic drug monitoring (ALLEZ, FRANCE) Perioperative management of CD: how to prepare Perioperative management of CD: how to prepare

patients for surgery (FORBES, UK)patients for surgery (FORBES, UK) Perioperative management of CD: postoperative Perioperative management of CD: postoperative

prevention of recurrence (REGUEIRO, USA) prevention of recurrence (REGUEIRO, USA) Medical treatment of severe colitis (LAHARIE, FRANCE) Medical treatment of severe colitis (LAHARIE, FRANCE)

I COSTII COSTI

INFLIXIMAB 300mg/2 mesi= COSTO/ANNO 10000 INFLIXIMAB 300mg/2 mesi= COSTO/ANNO 10000 €€ 400mg/ 2mesi= COSTO/ANNO 13300 400mg/ 2mesi= COSTO/ANNO 13300 €€

ADALIMUMAB 40 mg/2 sett= COSTO/anno: 13.300 ADALIMUMAB 40 mg/2 sett= COSTO/anno: 13.300 €€

Un giorno di ricovero in ospedale: in media 500 Un giorno di ricovero in ospedale: in media 500 €€/die/die

Un intervento chirurgico VLC sull’addome= 2000/5000 Un intervento chirurgico VLC sull’addome= 2000/5000 €€

CD: Evidence based Anti-TNF efficacyCD: Evidence based Anti-TNF efficacy

Anti TNF treatment have been prove effective Anti TNF treatment have been prove effective both as an induction and maintenance therapy both as an induction and maintenance therapy in :in :

1)1) Active luminal disease Active luminal disease

2)2) Peri-anal fistuling disease Peri-anal fistuling disease

3)3) Steroid-naive, dependent or refractory disease Steroid-naive, dependent or refractory disease

4)4) Immunosoppressant-naive or refractory disease Immunosoppressant-naive or refractory disease

Oussalah, Curr Drug Targets 2010Oussalah, Curr Drug Targets 2010

Induction and maintenance Induction and maintenance of remission in moderate-to-severe of remission in moderate-to-severe steroid-refractory or dependent CDsteroid-refractory or dependent CD

IG-IBD Statement 4AIG-IBD Statement 4A

Anti-TNF agents are a valuable option Anti-TNF agents are a valuable option in moderate-to-severe steroid- in moderate-to-severe steroid- refractory or dependent CD refractory or dependent CD

Thiopurines could be added in naïve Thiopurines could be added in naïve patientspatients

Adalimumab can be used as a second Adalimumab can be used as a second line treatment in patients with primary line treatment in patients with primary

failures to infliximab or with loss of failures to infliximab or with loss of response or intolerance to infliximabresponse or intolerance to infliximab

Maintenance of remission in luminal CDMaintenance of remission in luminal CD

IG-IBD Statement 4BIG-IBD Statement 4B Anti-TNF agents are effective for maintenance of remission Anti-TNF agents are effective for maintenance of remission

up to 1 year in patients with clinical response to induction up to 1 year in patients with clinical response to induction therapytherapy

Anti-TNF agents should be the treatment of choice for Anti-TNF agents should be the treatment of choice for patients who have failed maintenance strategies with patients who have failed maintenance strategies with

immuno- suppressantsimmuno- suppressants

Management of perianal complex fistulasManagement of perianal complex fistulas

IG-IBD Statement 5DIG-IBD Statement 5D ““Cone-like” fistulectomy of each fistula tract should firstly be Cone-like” fistulectomy of each fistula tract should firstly be

performed with sparing of sphincteric structures performed with sparing of sphincteric structures Seton placement should be recommended,the timing of Seton placement should be recommended,the timing of

removal depending on subsequent therapy.removal depending on subsequent therapy.Anti-TNF agents should be used as the first choice of Anti-TNF agents should be used as the first choice of

medical therapy for complex perianal CD medical therapy for complex perianal CD Combination with surgical therapy is recommended despite Combination with surgical therapy is recommended despite

a lack of clinical trialsa lack of clinical trialsAntibiotics and/or azathioprine/6-mercaptopurines should Antibiotics and/or azathioprine/6-mercaptopurines should

be used as a second line medical treatment,despite a be used as a second line medical treatment,despite a lack of clinical trials lack of clinical trials

Induction and maintenance ofInduction and maintenance of response/remission in moderate-to-severe response/remission in moderate-to-severe

steroid-refractory or steroid-dependent UCsteroid-refractory or steroid-dependent UC IG-IBD Statement 6A-BIG-IBD Statement 6A-B

Infliximab induction regimen can be used in patients with Infliximab induction regimen can be used in patients with moderate-to-severe UC who are refractory to systemic moderate-to-severe UC who are refractory to systemic corticosteroids and in corticosteroid-dependent patients corticosteroids and in corticosteroid-dependent patients who are intolerant/refractory to thiopurines.One year who are intolerant/refractory to thiopurines.One year scheduled treatment with Infliximab can be used in scheduled treatment with Infliximab can be used in patients who have responded to infliximab induction.patients who have responded to infliximab induction.

In patients who are thiopurine-naïve, maintenance therapy In patients who are thiopurine-naïve, maintenance therapy with thiopurines alone is a valuable option.The duration with thiopurines alone is a valuable option.The duration of the therapy over 1 year should be carefully evaluated of the therapy over 1 year should be carefully evaluated on a case-by-case basis Maintenance therapy with on a case-by-case basis Maintenance therapy with infliximab that achieves only response should be infliximab that achieves only response should be

carefully evaluated in the face of acarefully evaluated in the face of a colectomy colectomy

Induction and maintenance of response/remission in Induction and maintenance of response/remission in

severe steroids refractory UCsevere steroids refractory UC IG-IBD Statement 7AIG-IBD Statement 7A

Infliximab reduces colectomy rate within 3 months in Infliximab reduces colectomy rate within 3 months in steroid-refractory severe UCsteroid-refractory severe UC

A colectomy is recommended if there is no improvement A colectomy is recommended if there is no improvement within 5days[EL5,RG D]within 5days[EL5,RG D]. . Infliximab should be avoided in Infliximab should be avoided in patients with a complicated diseasepatients with a complicated disease

Reinfusions seem more effective than one single infusion to Reinfusions seem more effective than one single infusion to prevent early colectomy, but there is insufficient evidence to prevent early colectomy, but there is insufficient evidence to provide recommendations on the ideal dosing provide recommendations on the ideal dosing schedule.Antibiotic prophylaxis against opportunistic schedule.Antibiotic prophylaxis against opportunistic infections is suggestedinfections is suggested

““INTERAZIONI” nell’outcome delle M.I.C.I.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 2006Wolters F, et al SJG 2006