Quando sospendere la terapia biologica ?

Claudio Bilardi

Modulo di Gastroenterologia Ospedale Villa Scassi

Genova, 26 Novembre 2011, Hotel Sheraton

ECCO Statement 6H (Crohn Disease)

No recommendation can be given for the duration of treatment with methotrexate or anti-TNF agents, although prolonged use of these medications may be considered if needed [EL3, RG C]. Potential risksand benefits should be discussed on an individual basis.

Dignass A et al, Journal of Crohn's and Colitis, 2010

ECCO statement 6 K (ulcerative Colitis)

Due to lack of evidence, no recommendation can be given for the duration of treatment with azathioprine or infliximab, although prolonged use of these medications may be considered if needed [EL4, RG D]

Travis S.P.I et al, Journal of Crohn's and Colitis, 2008

ECCO Guidelines

IG-IBD Statement 6B (Ulcerative Colitis)

One year scheduled treatment with Infliximab can be used in patients who have responded to infliximab induction [EL 1b,RG A]. In patients who are thiopurine-naïve, maintenance therapy with thiopurines alone is a valuable option [EL 5, RG D]. The duration of the therapy over 1 year should be carefully evaluated on a case-by-case basis [EL 4, RG C]. Maintenance therapy with infliximab that achieves only response should be carefully evaluated in the face of a colectomy [EL 5, RG D]

A. Orlando and IG-IBD, Digestive and Liver Disease, 2011

IG-IBD Statement 4C (Crohn’s disease)

Open experiences have reported long-term effectiveness and safety of anti-TNF_ agents; however, the duration of the therapy over 1 year should be carefully evaluated on a case-by-case basis [EL 4, RG C]

Italian Guidelines

Key questions to address when starting biologicals

1) What is the aim / endpoint of therapy in my patient?

• Steroid discontinuation and steroid-free remission?

• Fistula closure?

• Bring patient in deep remission?

• Control of extra-intestinal disease?

• Mucosal healing, QoL?

2) Are there any contra-indications?

• e.g. active infection…

3) Do I have to undertake specific actions to maximize response?

• Do I need to optimize therapy?

• Should I stop certain therapies?

• Role of smoking …

Treatment goals

Induction of remission

wk 4: 35-40% (ACCENT I&II, CLASSIC 1); wk 26 (CS-free): 50% (SONIC)

Maintenance of remission

1 yr: 35-40% (ACCENT I&II, CHARM, SONIC); 3yr: 30% (ADHERE)

Steroid-sparing

1 yr: 25-30% (ACCENT I, CHARM), 40% (GETAID); 3yr: 30% (ADHERE)

Mucosal healing (ACCENT I, SONIC, EXTEND, Local cohorts)

Reduction of hospitalizations and surgeries (ACCENT I&II, CHARM)

Improvement of QoL (ACCENT I&II, CHARM)

Anti-TNF alpha in CDInduction/Maintenance of remission

and added clinical benefits

N=172 N=215N=113

Infliximab (ACCENT I)Adalimumab (CHARM)Certolizumab (PRECISE 2)Placebo

0

20

40

60

80

100

% p

azi e

nt i

Remissione clinica in terapia con anti-TNF-

Long-term outcome of treatment with IFX in CD

Stop of IFX70/547 patients => side effects (12.8%)

Stop of IFX 12/547 patient => other reasons (2.2%)

Stop of IFX118/547 patients => LoR (21.6%)

237/547 CD patients still on IFX

with sustained benefit at the end of follow-up (43.3%)

110/547 CD patients stopped IFX

due to remission (20.1%); 84 of them (76.4%) still in remission at the end of follow-up

547 CD patients

Sustained clinical benefit in 347/547 patients

(63.4%) Primary end pointSchnitzler F, et al. Gut 2008Median follow up: 55 months (IQR 27-83)

D ’ Haens GR et al, Lancet, 2008

MH at 2 years predicted stable clinical remission

68%

35%

0

20

40

60

80

100

MH No MH

% s

tabj

e cl

inic

al r

emis

sion

Armuzzi A, et al.UEGW 2009

Long-term IFX maintenance therapyMucosal healing and surgeries in

CD

5545

MH (n=60) No MH (n=49)

MH in 109 CD

Median FU: 44 months (IQR 33-63)

Median N infusion: 15 (IQR 12-20)

Median time on scheduled IFX: 26 months (IQR 20-39)

11,9

3,7

33

51,4

0

10

20

30

40

50

60

No MH MH%

Surgery No Surgery

13 36 564

P= 0.001

Schnitzler F, et al. IBD 2009

Mucosal healing and long term outcome of Infliximab maintenance

therapy (Leuven)

45,432,2

22,4

Complete MH (n=83)Partial MH (n=41)No MH (n=59)

Abdominal surgeries

Clinical benefit

MH

No MH

MH

No MH

Baert F, et al. Gastroenterology 2009

Mucosal healing in CD at year 2 predictssustained clinical remission during year

3 + 4

Percen

tage o

f patien

ts (%)

70,8

27,3

0

20

40

60

80

100

Complete mucosal healing (SES=0 at year 2)Endoscopic activity (SES=1-9 at year 2)

17/24

P=0.036

OR 4.35 (95% CI 1.1-20.8)

6/22 4,222,7

020406080

100

Complete mucosal healing (SES=0 at year 2)Endoscopic activity (SES=1-9 at year 2)

P=0.089

1/245/22

New or active draining fistula during Year 3+4

Clinical remission (CDAI<150, no steroids, no resections)

during Year 3+4

49 patients from SUTD trial underwent colonoscopy at year 2

FU during year 3 and 4

Crohn's disease flares per patient according to mucosal healing status.

Baert FJ et al Gastroenterology 2009

Early normalization of CRP level and better sustained response

Jurgen M et al, Clinical Gastroenterology and Hepatology, 2011

CRP level at baseline and at time of first endoscopy and mucosal healing status

Jurgen M et al, Clinical Gastroenterology and Hepatology, 2011

Armuzzi A, et al. UEGW 2009

Long-term scheduled treatment with IFX in CD

Relapse after IFX withdrawal

43 CD24 (19-34 IQR) months of median IFX scheduled treatment13 (10-19 IQR) months of median FU since suspension21 (48.8%) CD relapse

MH and low CRP at discontinuationpositive predictors of sustained remission after IFX withdrawal.

MH

No MH

Low CRP

High CRP

Maintenance of clinical benefit in Crohn’s disease patients after discontinuation of infliximab

Waugh A.W G et al, Aliment Pharm Ther, 2010

Between July 2000 and July 2007, 354 patients with Crohn’s disease completed a three-dose induction regime with infliximab and entered into maintenance infliximab dosing every 8 weeks

Of those patients who entered into maintenance infliximab treatment, a total of 48 patients were eligible to be included in the cohort for this study if theyhad responded to infliximab, maintained a stable corticosteroid-free clinical benefit for at least 6 months and discontinued the infliximab for reasons other than loss of response.

Maintenance of clinical benefit in Crohn’s disease patients after discontinuation of infliximab

Waugh A.W G et al, Aliment Pharm Ther, 2010

At the time of infliximab discontinuance, 44% of the patients were receiving azathioprine, 19% methotrexate and 4% mercaptopurine as concomitant immunosuppressive therapy.

Maintenance of clinical benefit in Crohn’s disease patients after discontinuation of infliximab

Waugh A.W G et al, Aliment Pharm Ther, 2010

Kaplan–Meier analysis of the proportion of patients with sustained clinical benefit demonstrated that 50% relapsed within 477 days after infliximab discontinuance. In contrast, 35% of patients remained well, and without clinical relapse, up to the end of the nearly 7-year follow-up.

STORI trial (GETAID)IFX discontinuation in CD patients in stable

remission

Louis E, et al DDW 2009

Aims & Methods:

-To assess the risk and identify factors of CD relapse in a prospective cohort study of 115 patients with luminal CD

-Patients received last IFX infusion at baseline and were followed up at week 2 and every 2 months. IS was kept at a stable dosage

-Discontinuation of IFX after IFX + IS > 1 yr and have a stable remission wihtout steroids for > 6 months

-Median FU: 12 months

-Demographic, clinical and biological factors were evaluated for their potential association with the time-to-relapse through log-rank method and hazard ratio (HR) was estimated through Cox model

Predictive factor of relapse (multivariate) HR

P

Hb ≤14.5 g/dl/ > 14.5 g/dl 4.68 (1.4-15.3) 0.0016

IFX through levels ≥ 2/ <2 mg/ml 2.94 (1.3-6.7) 0.0058

CRP ≥ 5 / < 5 mg/L 3.79(1.9-7.4) 0.0002

CDEIS ≥ 2 / < 2 3.05 (1.6-5.7) 0.0007

Louis E, et al DDW 2009

STORI trial (GETAID)IFX discontinuation in CD patients in stable

remission

STORI trial (GETAID)IFX discontinuation in CD patients in stable

remission

Louis E, et al DDW 2009

Results:

52 relapses recorded

5 withdrawal before re-treatment (patient (n=4) or investigator decision

47 re-treatments

37 evaluated responsed to re-treatments at 4 weeks

36/37 remissions with no complications

Endoscopic (CDEIS) and biological markers (including hemoglobin, US CRP, IFX trough levels) of inflammation permitted the identification of patients with very low or very high risk of relapse

Endoscopic and biological markers of activity are low in patients with stable clinical remission under combined IFX + IS therapy

More than half of the patients have not relapsed one year after IFX discontinuation

In relapsing patients, re-treatment with IFX was successful and well tolerated in almost all patients

Louis E, et al DDW 2009

STORI trial (GETAID)IFX discontinuation in CD patients in stable

remission

Conclusions:

Conclusioni

Le linee guida (sia italiane che internazionali) non indicano quale debba essere la durata del trattamento

Pochi studi hanno analizzato questo aspetto mettendo in evidenza il concetto di remissione profonda ed identificando alcuni markers del probabile mantenimento della risposta.

E’ necessario sviluppare altri fattori predittivi che ci aiutino ad individuare il paziente candidato alla sospensione della terapia