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
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 factoralpha antagonist therapy in Inflammatory Bowel Disease”
(Digestive and Liver Disease 2010)
TERAPIA TRADIZIONALE
 MESALAZINA
 STEROIDI
 AZATIOPRINA (6MP)
 CICLOSPORINA
 METOTREXATE
 ANTIBIOTICI
100
REFRACTORY
80
60
DEPENDENCY
40
20
RESPONSE
0
1 month
1 year
Munkholm 1994, Faubion 2001, Ho, 2006, Papi
2007
STEROIDI: LIMITI
TROPPI EFFETTI COLLATERALI
(ATTENTI ALL’AUTOPRESCRIZIONE!)
Cardiovascolari: ipertensione
Dermatologici: Ecchimosi, petecchie, strie rubre, acne
Endocrino-metabolici (Soppressione asse ipotalamoipofisi-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
IMMUNOSOPPRESSORI: QUANDO?
consensus E.C.C.O. 2010
1)
2)
3)
4)
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
Azathioprine is not altering the natural
history of Crohn’s disease
60
Immosuppressant Use P<0.001
50
Resection p=0.5
Stoma p=0.7
40
30
20
10
0
1978-1982
1983-1987
1988-1992
1993-1997
1998-2002
Cosnes J et al Gut 2005
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)
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%
Medications
10.2%
Hay JW, et al. J Clin Gastroenterol. 1992; 14:309
Surgery
46.2%
Natural history of IBD

Risk of stricturing and perforating complications
in CD is above 50% over 10 - 20 years (peyrinbiroulet 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
10 - 20 years (hoie 2007 gastroenterology)

Increased risk of colon cancer associated with
chronic uncontrolled colonic inflammation (rutter
gastroenterology 2004)
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?
IFX and ADA STUDIES
INFLIXIMAB 1999 (CD and UC):
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
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
ECCO indications for anti TNF in CD and UC
a)
b)
c)
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 2008-2010
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
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
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 2006
LOLY SCAND J GASTR 2008
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): 2609-2615
TAILORED
AND
NOW? 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 2010
TRAVIS J Crohn Colitis 2008
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
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
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
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
ACCENT I
Endoscopic healing reduces the risk of
surgery and hospitalisation
Rutgeerts et al. Gastrointestinal Endoscopy 2006
Crohn – IFX – Step-up/Top-down trial
follow-up
Mucosal Healing in CD at Year 2 Predicts
Sustained Clinical Remission
Patients in remission years 3-4
(%)
49 patients from SUTD trial underwent colonoscopy at year 2
and were followed-up through year 3 and 4
100%
75%
p=0.036
OR=6.48
(95%CI 1.8-23.4)
p=0.032
OR=7.5
(95%CI 1.9-29.3)
p=0.009
OR=0.148
(95%CI 0.016-1.38)
50%
25%
0%
Remission off-GCS
SES-CD = 0 (n=24)
SES-CD 1-9 (n=22)
71%
27%
Remission off-GCS & offIFX
63%
18%
New or active draining
fistulae
4%
23%
Baert F, et al. Gastroenterology 2010
Massimizzazione efficacia clinica anti-TNF
MC studio SONIC
100%
*
*
75%
Percent of patients
78,7%
74,1%
66,0%
*
*
50%
56,8%
72,2%
62,7%
54,7%
44,4%
30,6%
25%
0%
CS-free REMISSION w26
Clinical REMISSION w50
AZA
IFX
D100 RESPONSE w50
IFX+AZA
* p<0.05 vs placebo
Colombel JF, et al. NEJM 2010; 362:1383-95
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
UC: Predictive Factors of
Colectomy
Predictive Factor
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)
0.01
Moderate to severe
UC with duration ≤3
years
0.36 (0.23–0.57)
<0.001
Sandborn Gastroenterology. 2009
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 combotherapy with anti-TNF and IS should preferably be introduced
and decrease the risk of cancer and surgery (mucosal healing)
PANACCIONE, J CROHN COLITIS 2011
Massimizzazione efficacia clinica anti-TNF
RCU studio SUCCESS
*
*
*
*
*
* p<0.05 vs placebo
Panaccione R et al. J Crohns Colitis 2011
Surgery requirements according to
mucosal healing status
Ulcerative colitis
Pts with MH at 1 year
P=0.10
Pts without MH at 1 year
Proportion of UC Patients
Not Colectomised
Proportion of CD Patients
Not Resected
Crohn’s disease
Pts with MH at 1 year
P=0.02
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):412-422.
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
CAUTO OTTIMISMO
STOP

FINE
G.L.I.B.D
IBD UNIT
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’
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
GRADES OF RECOMMENDATION ECCO
A (Systematic review
CD
UC
18%
20%
25%
24%
20%
24%
37%
32%
with homogeneity of
randomised
controlled)
B (Validating cohort
study with good
reference standards)
C (Case–control study,
poor or non-independent
reference standard)
D(Expert opinion
without explicit critical
appraisal)
GRADES OF RECOMMENDATION IG-IBD
A (Systematic review with
homogeneity of randomised
controlled)
B (Validating cohort study
with good reference
standards)
C (Case–control study, poor
or non-independent
reference standard)
12%
D (Expert opinion without
explicit critical appraisal)
41%
29%
18%
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.
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)
I COSTI

INFLIXIMAB 300mg/2 mesi= COSTO/ANNO 10000 €
400mg/ 2mesi= COSTO/ANNO 13300 €

ADALIMUMAB 40 mg/2 sett= COSTO/anno: 13.300 €

Un giorno di ricovero in ospedale: in media 500 €/die

Un intervento chirurgico VLC sull’addome= 2000/5000 €
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
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 steroidrefractory 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
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
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
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
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
“INTERAZIONI” nell’outcome delle M.I.C.I.
Fattori
genotipici
TERAPIA
Fenotipo
Fattori
demografici
Decorso
Risultato
Fattori
psicosociali
Fattori ambientali
Wolters F, et al SJG 2006