La terapia con anti TNF alfa nella Malattia di Crohn - Gastrolearning®

La terapia con anti TNF alfa nella Malattia di Crohn

Relatore: Dott. A. Orlando (Palermo)

LUNEDI 9 FEBBRAIOORE 15.30

Goals of therapy in IBDs

• Inducing/maintaining remission

• Prevention of PO recurrence

• Steroid weaning

• Restore and maintain nutrition

• Maintain quality of life

• Select optimal timing for surgery

10 years ago …

• Early and rapid treatment

• Prevention of PO lesions

• Minimize drug toxicity (optimal safety)

• Sustained mucosal healing

• Prevention complications

• Prevention hospitalisations and surgeries

• Long term steroid-free (deep) remission

• Prevention or Reduce long term disability

... today

Treat symptoms,induce remission and

treat on flare

Treat symptomsand lesions (early)

with long term strategy

Knowledge Required To Treat Patients With Crohn’s Disease (or UC)

1. Classification2. Natural History3. Results of RCTs

• High Placebo Remission rate

18% (95% CI 14%–24%) (range 0%-50%) Su 2004

17% (95% CI 13 – 21%) (range 0%-34%) Tinè 2008

• No clinical trial ever completely reflects what is

happening in an individualized patient

Lloyd F. Mayer

RG A 12% 12%

RG B 36% 29%

RG C 19% 18%

RG D 32% 40%

115 statements234 reccomendations(diagnosis & management)

47 statements103 reccomendations(anti TNF therapy)

4. Guidelines

The majority of reccomendations are based on expert opionions !

Crohn’s Disease is not a 6-week diseases !

Lifelong management and strategies are necessary

Evolution of Therapeutic Approach in IBDs

Immunomodulators

Biologics

Surgery

Aminosalycilates Antibiotics

Systemic steroids

MILD

SEVERE

MODERATE

Topically acting steroids

New drugs

New strategies

Tailored treatment

Time trends in supply 5-ASA, IM, steroid (left axis) and infliximab prevalence (right axis) for Crohn’s disease

Time trends in the prevalence of prolonged steroid exposure and in the rates of hospitalization and surgery for

Crohn’s disease

Systemic Corticosteroids Story

Observational studies 1990-2000

Munkholm 1994, Faubion 2001 Lichtenstein, 2006

Population Based Studies TREAT Registry

100

20

40

60

80

0

1 month 1 year

RESPONSE

REFRACTORY

RESPONSE

REFRACTORY

DEPENDENCY

SURGERY

100

20

40

60

80

0

1 month 1 year

RESPONSE

REFRACTORY

RESPONSE

REFRACTORY

DEPENDENCY

SURGERY

Timeline with the milestones in CTs development in CD before the advent on anti-TNF agents

Hindryckx P et al JCC 2014 May

CTs: Clinical Trials; RCT: Randomized controlled trials, NCCDS: National Cooperative Crohn’s disease study; CDAI: Crohn’s disease activity index; ECCDS: European cooperative Crohnìs disease study; CDEIS: Crohn’s

disease endoscopic activity index of severity

Definition of Outcomes

Luminal Crohn’s disease

Clinical responseCDAI reduction > 70 points from the baseline

CDAI reduction > 70 points + at least 25% reduction from the baselineClinical remission

CDAI < 150Steroid sparing

Clinical remission (CDAI < 150) and off steroidsMucosal healing

Mucosal ulceration at wk 0 and no mucosal ulceration at follow-upDeep remission

Defined as clinical remission (CDAI <150) and complete MH

Orlando A. et al. Digestive and Liver Disease 2011; 43: 1–20

GOALS OF MANAGEMENT IN CROHN’S DISEASE


Orlando A. et al. Digestive and Liver Disease 2011; 43: 1–20



Annese V. et al. Journal of Crohn's and Colitis (2013) 7, 982–1018

GOALS OF MANAGEMENT IN IBD

Mary JY et al. Gut 1989;30:983-9Daperno M. et al. Gastrointest Endosc 2004;60:505-12

MUCOSAL HEALING IN CROHN’S DISEASE

Overview of the evolution of primary endpoints of CTs in luminal CD

Hindryckx P et al JCC 2014 May

Forest plot of randomized controlled trials of anti-TNFα antibodies vs placebo in inducing remission in active

luminal CD

Forest plot of randomized controlled trials of anti-TNFα antibodies vs placebo in preventing relapse in

quiescent CD

Ford et al. Am J Gastroenterol. 2011;106:644-59

0

5

10

15

20

25

30

35

ACCENT I51% steroids at entry

pla

CHARM44% steroids at entry

pla

5mg/kg

10mg/kg40mg eow

40mg weekly

STEROID SPARING EFFECT(CORTICOSTEROID FREE REMISSION AT 1 YEAR)

90 -

80 -

70 -

60 -

50 -

40 -

30 -

20 -

10 -

0 -

Response rateRemission rate

Week 6

% p

atie

nts

45.5%

100 -

45.5%

90 -

80 -

70 -

60 -

50 -

40 -

30 -

20 -

10 -

0 -

Response rateRemission rate

% p

atie

nts 64.5%

100 -

16,4%

End of follow up (14.6 ± 10 months)

Orlando A. et al. Inflamm Bowel Dis 2012;18:826-831

110 steroid-dependent pts treated with ADA (80/40 or 160/80 mg eow, followed by 40 mg eow). Clinical remission: steroid discontinuation without symptomatic recurrence.

Clinical response: reduction or maintenance of the initial CDAI value reducing steroid dosage but without its discontinuation.

Orlando A et al. Dig Liver Dis. 2011; 43:1-20Van Assche G et al JCC 2010

Response to anti-TNFs in Pivotal Trials(All randomized patients)

CertolizumabPRECISE 2(400 mg/4Wk)

InfliximabACCENT 1(5 mg/kg/8Wk)

AdalimumabCHARM

(40 mg/2Wk)

PrimaryNon Responders

SecondaryNon Responders

LongtermResponders

100

Remission

70

Remission

70

100

Remission

%

64

40

290

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56

32

58

28

24 190

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56

60

32 26

25 24 220

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56

%

%

weeks

1)

2)

3)

smoking should be discouraged in all patients

Maintenance of medically induced remission guidelines

Evolving goals of therapy for Crohn’s disease:“sustained steroid clinical free remission”

Response

Steroid freeRemission

Goal Clinical parameters

Improved symptoms

No symptoms

Normal labs

Outcomes

Improved QoL

Decreased hospitalisation

SUSTAINED

24

How will Sustained Clinical-Steroid Free Remission as a management goal affect patients

with early or late disease?

• Disease duration may alter treatment goals– Late disease has inflammatory and non-inflammatory

symptoms• Definition of SCSFR may be different for different patient

types– e.g. absence of symptoms in early CD, and improvement in

symptoms in late CD

2400 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228

0

100

90

80

70

60

50

40

30

20

10

Long-term evolution of Crohn’s disease behaviour

Cosnes J, et al. Inflamm Bowel Dis 2002;8:244–50

Penetrating

Stricturing

Cu

mu

lati

ve p

rob

abili

ty o

f re

mai

nin

g

free

of

com

plic

atio

ns

(%)

Inflammatory

Months

372,002 552 229 95n = Patients at risk:

Start therapy

The earlier, the better ?

1) Indirect evidence from rheumatology – early RA (e.g. BeSt Study)

2) Indirect evidence from pediatric studies

3) Indirect evidence and post-hoc analyses from adult studies

4) SUTD, SONIC, POST-OP

Longitudinal course of rheumatoid arthritis

Kirwan JR. J Rheumatol 2001Disease duration (years)

DisabilityRadiographsInflammationS

ever

ity

(arb

itra

ry u

nit

s)

0 5 10 15 20 25 30

Early RA Intermediate LateKlareskog L, et al. Lancet 2009

Anti-TNF alpha in pediatric and adult luminal CD

Hanauer S, et al. Lancet 2002; Hyams J, et al. Gastroenterology 2007; Colombel JF, et al Gastroenterology 2007; Hyams J, et al. ECCO 2011

39

28

40

59,655,8

39

57

0

10

20

30

40

50

60

70

80

90

100

IFX ACCENT/REACHwk 30 remission

IFX ACCENT/REACHwk 54 remission

ADA CHARM/PED wk 26 remission

% r

em

issi

on

Adult CD Ped CD

Disease duration: adult ~8 yr – pediatric ~2 yr

Adapted from Schreiber S, et al. Gastroenterol 2007;132(4 Suppl 2):A-147

Patients in remission, week 56: <2 years placebo n=4/23, adalimumab n=20/39; 2 to <5 years placebo n=4/36, adalimumab n=25/57; 5 years placebo n=12/111, adalimumab n=82/233. Data are from randomised responders

Patients received induction therapy of adalimumab 80 mg (week 0) followed by 40 mg (week 2) and were randomised at week 4

Week 56

0

20

40

60

80

100

Patie

nts

with

rem

issi

on (%

)

23n= 39<2 years

17%

51%

36 572 to <5 years

11%

44%

111 233≥5 years

11%

35%

p=0.014 p=0.001 p<0.001

Placebo

All adalimumab

Time from diagnosis to anti-TNF

CHARM: Early Adalimumab Use is Associated with Higher Rate of Remission than Later Use

Post-hoc analysis

IFX (0,2,6 wk)

AZA (2-2.5 mg/kg)

133 CD < 4 yrs durationCDAI>220

GCS/ISS/IFX naive

Failure

Failure

STEP-UP n=66

Bud 9 mg/die

mPred 32mg/die

ISS

IFX

TOP DOWN n=67

IFX

CS

Primary endpoint CDAI<150 off steroids, no resection

D’Haens G, et al. Lancet 2008

Early combined immunosuppression vs conventional management of newly diagnosed CD

and follow up through year 3 and 4

73,1

30,4

0

20

40

60

80

100

TD SU

%

MH at 2 years

p=0.003

62,5

18,2

0

20

40

60

80

100

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

OR 4.88 (95% CI 1.1-20.8) P=0.032

Clinical remission, no steroids, no resections and no anti-TNF

through Year 3+4

Baert F, et al. Gastroenterology 2010

p=0.031 (log-rank test)

0

20

40

60

80

100

14 20 26 32 38 44 50 56 62 68 74 80 86 92 98 104Weeks after randomisation

Pa

tie

nts

wit

h n

o r

ela

ps

e (

%)

//

Top downStep up

Weeks from diagnosis to treatment2.0 (1–5) - 2.5 (1–11)

Early treatment in Crohn’s disease

Orlando A et al. Dig Liver Dis. 2011; 43:1-20

Van Assche G et al JCC 2010

OR (95%CI)

0,2 0,5 1 2 5 10 100 1000

Precise II Response 26 wks

Precise I Response wk 6 & 26

Precise1 Response wk 6

Gain Remission 4 wks

Classic II (open cohort) Remission 56 wks

Classic II (randomised cohort) Remission 56 wks

Charm Remission 56 wks

Charm Remission 26 wks

Classic 1 Remission 4 wks

Rutgeerts 1999 Response 48 wks

ACCENT I Remission 54 wks

ACCENT I Response 54 wks

ConcomitantImmunomodulators

No concomitantImmunomodulators

ODDS RATIO FOR RESPONSE/REMISSION IN PATIENTS WITH AND WITHOUT CONCOMITANT IMMUNOMODULATORSSubgroup analysis from RCTs Infliximab Adalimumab & Certolizumab

“It’s OK to perform subgroup analysis…….

as long as you don’t believe the results”

Rory Collins University of Oxford

Karmiris K, et al. Gastroenterology 2009

Anti-TNF alpha and concomitant IM (Leuven)

Schnitzler F, et al. Gut 2009

IFX ADA

• > 21 years of age

• Active CD (CDAI 220-450)

• ISS and biologics naive

• steroid-dependent

(CDAI >220 after steroid dose reduction)

• being considered for a second steroid

course within 12 mo

• No response to mesalamine

(≥2.4 g for 4 wks)

• No response to budesonide

(≥6 mg for 4 wks)

SONIC

(n. 508)

50

n. 204

To combine or not to combine ?

Van Assche G et al JCC 2010 Orlando A et al. Dig Liver Dis. 2011; 43:1-20

All patients: 854Patients treated with corticosteroids at baseline: 376 (44%)

Colombel et al. Gastroenterology 2007;132:52-65

Up to 4 years!!

Panaccione R et al Aliment Pharmacol Ther 2013

Long-Term Maintenance of Clinical Remission(ADHERE)

Panaccione et al. Aliment Pharmacol Ther .Sep 2013

Sustained steroid-free clinical remission with ADA

after 4 years of therapy for Crohn’s disease

(ADHERE)

Patients who achieved corticosteroid-free clinical remission at the end of CHARM

and maintained corticosteroid-free clinical remission over time.

Patients who received a reinduction

dosage (160/80 mg)

Clinical remission

26/110 (24%)

13/26 (50%)

Patients who received a weekly

maintaining treatment (40 mg)

Clinical remission

28/110 (25%)

14/28 (50%)

Patients who obtained a mucosal healing

(60 patients underwent colonoscopy) 15/60 (25%)

Patients who were switched to infliximab

Clinical remission

16/110 (14%)

11/16 (69%)

Patients who were operated on 19/110 (17%)

Patients in maintaining treatment: 54/110 (49%)Patients who stopped treatment because of mucosal healing: 6/110 (5,4%)

Results

Long Term Adalimumab Efficacy In Steroid-dependent Crohn’s Disease Patients

100

90

80

70

60

50

40

30

20

10

0

Patie

nts

(%)

32%

54%

Follow up (38.6 ± 10 months)

14%

60/110 35/110 15/110

Maintaining clinical remission

Stop for ineffectiveness

Stop for side effects

Orlando A. et al. Unpublished data 2013

Up to 3 years!!

Results


Univariable analysis

p-value OR (95% CI)

Induction dosage vs maintaining clinical remission p = 0.06 2.01 (0.944-4.266)

Results


Univariable analysis

p-value OR (95% CI)

Induction dosage vs maintaining clinical remission p = 0.06 2.01 (0.944-4.266)

Induction dosage vs treatment with infliximab p = 0.73 1.22 (0.39–3.76)

Induction dosage vs mucosal healing p = 0.27 1.98 (0.57-6.85)

Induction dosage vs surgery at follow up p = 0.04 0.311 (0.969-0.998)

Induction dosage vs response to infliximab P <0.001 6 (1.01-35.91)

A higher induction regimen (160/80 mg) was associated with a lower risk of surgery

A lower induction regimen (80/40 mg) was associated with a best response to infliximab

Orlando A. et al. Unpublished data 2013

Sustained benefit from IFX/ADA in CD (Leuven)

Schnitzler F, et al. Gut 2009

Drop of CRP as predictor of sustained clinical benefit

Karmiris K, et al. Gastroenterology 2009

168 CD patients with LOR or intolerant to IFX treated with ADA: 61.5% with

sustained clinical benefit at median FU (20.4 months IQR 12-30)

547 CD treated with IFX: 63.4% with sustained clinical benefit at median FU

(55 months IQR 27-83);

Jurgens M, et al. CGH 2011

Patients with relapse leading to stop of therapy

All patients

All patients with clinical relapse

Tight-control: CRP levels in responders and non-responders to infliximab

BIOLOGICS IN CROHN’S DISEASEAnti-TNFα antibodies vs. placebo in healing of fistulizing CD

Ford et al. Am J Gastroenterol. 2011;106:644-59

0

5

10

15

20

25

30

35

40

45

50

23%

Placebo

Infliximab

Chiusura fistola a 54 settimane

Risposta a 54 settimane

ACCENT II: N Engl J Med 2004

46%

19%

36%

Infliximab 5 mg/kg Sett. 0 – 2 -6

Sett. 14 Randomizzatione dei responders:

- Infliximab 5 mg/kg - Placebo

Infliximab

(n=282)

% p

azi

en

ti

(n=195) (175 fistole perianali)

Malattia perianale – Terapia con anti-TNF

Ascesso perianale nel 12% dei pazienti trattati con Infliximab

ADA combined with CIPRO is superior to ADA monotherapy in perianal fistula closure in Crohn’s disease: a randomised,

double-blind, placebo controlled trial (ADAFI)

76 CD patients with active

perianal fistulusing disease.

ADA induction 160/80 w 0,2 and after 40 eow with CIPRO o Placebo.

Primary outcome: response and

remissionat w 12

Univariate analysis showed that outcome was not influenced by any of the patients caracteristics

Dewint P et al. GUT 2014; 63:292-99

Biological immunomodulators improve the healing rate insurgically treated perianal Crohn’s fistulas

(Cleveland Clinic)

El Gazzaz G et al. Colorectal Disease 2012; 14: 1217-23

218 CD patients with active

perianal fistulusing disease.

Group A: surgery 54 %

Group B: surgery+biologics

46%

Mean Follow-up 3.2 ys

Orlando A et al. Disease. Dig Liver Dis. 2010 Sep 13

MUCOSAL HEALING AND ANTI-TNFα

Beppu T. et al. Digestive Endoscopy 2015; 27: 73–81

Rutgeerts P et al. Gastroenterology 2012;142:1102-1111


135 pts received ADA160/80 mg at weeks 0/2 At week 4 they were assigned to ADA 40 mg or placebo eow through

week 52

Colombel JG et al. N Engl J Med 2010;362:1383-95


D'Haens G et al. Lancet 2008;371:660–7

Peyrin-Biroulet L. et al. Journal of Crohn's and Colitis (2011) 5, 477–483

Baert F et al. Gastroenterology 2010;138:463–8

Schnitzler F et al. Inflamm Bowel Dis 2009;15:1295–1301

Schnitzler F. et al. Inflamm Bowel Dis 2009;15:1295–1301

SHADOWS ON MUCOSAL HEALING

Rutgeerts P et al. Gastrointest Endosc 2006;63:433-42


?

Björkesten CG, Inflamm Bowel Dis. 2011;17:947-53


?

Bouguen G et al. Clin Gastroenterol Hepatol 2014;12:978-85


?

Solberg IC, et al. Clin Gastroenterol Hepatol 2007;5:1430–8

IBSEN: disease course in Crohn’s disease over 10 years

Dis

ease

acti

vity

0 1010Years 0 Years

43% 19%

3% 32%

Missing data, 3%

However… Management Must Be Tailored to the Individual Patient

Disease severity Patient’s expectation

Benefit / risk of treatmentPatient’s preference

Patient Selection:

Tailored

• Disease location and behaviour– Rectal disease– Perianal lesions– Extensive small bowel disease– Severe upper gastro-intestinal disease– Severe extraintestinal manifestations– Deep ulcers

• Worsening factors– Smoking– Young age at diagnosis– Genetic and serological profile (future?)– Steroids for 1st flare

Clinical features suggesting a « bad » Crohn’s disease

“Optimized step-up or targeted top-down strategies”

Munkholm P. Scand J Gastroenterol 1995;30:699–700; Louis E. Gut 2003;52:552–7; Lakatos P. World J Gastroenterol 2009;15:3504–10; Henckaerts L. Clin Gastroenterol Hepatol 2009;7:972–80; Romberg MJ. Am J Gastroenterol 2009;104:371–83; Chow D. Inflamm Bowel Dis 2009;15:551–7; Hellers G. Gut 1980;21:525–7; Beaugerie L. Gastroenterology

2006;130:650–6; Loly C. Scand J Gastroenterol 2008;43:948–54; Allez M. Am J Gastroenterol 2002;97:947–53

Possible approaches to achieve and long-term clinical remission in clinical practice?

1. Based on international expert opinion, Abbott IBD Ahead 2010 programme. 2. Colombel JF, et al. Accepted to ECCO 2011: PO69; 3. Colombel JF, et al. Gut 2010;59(Suppl 3):A188: P400 at UEGW 2010; 4. Panaccione R, et al. J Crohn’s Colitis 2009:3;S69: P148 at ECCO 2009; 5. Kamm MA, et al. J Crohn’s Colitis 2009;3:S43-4: P83 at ECCO 2009

• Identify patients likely to have a poor prognosis who may benefit from intensive therapy

• Optimise conventional therapy quickly1

• Introduce anti-TNF therapy in a timely manner to appropriate patients2,3

• Sustain efficacy in the longer term

– Sustained clinical and steroid-free remission4,5

• Monitor patients to maintain ‘tight control’

– Will be evaluated in appropriately designed clinical trials

CLINICAL PRACTICE

CLINICALCLINICALRESEARCHRESEARCH

(Sample Size)(Sample Size)

Differentdrug

dosages

Lengthof

therapy

Agelimit

Concomitant therapy

not permittedin the trials

Concomitant pathologies

Alterated organ function

DIVARICATION BETWEEN CLINICAL RESEARCH AND CLINICAL PRACTICE

Referral centres with different experience

Comorbidities

Malnutrition,Diseaseseverity,Surgery

Underlyingdisease

DIFFERENT RISK OF INFECTIONS IN IBD PATIENTS

Referral centre with different experience

- Increased prevalence ranges from 3-20 fold + ElderlyYoung

Age is a significant risk factor for opportunistic infections

1. Toruner M et al. Gastroenterology 2008;134: 929-9362. Rahier JF et al. Journal of Crohn’s and Colitis 2014; 8,443-68

2 categories of risk :

External to the patientsInherent to the patients

Exposure topathogens

Immunomodulatortherapy

Geographicclustering

Piogenic infections(Pneumonia, TBC,

urinary tract infections)

Viral infections

Immunomodulator therapyViral infections may occur with anti-TNFs, viruses are

more prominent with the thiopurines

Risk factors for opportunistic infections in IBD

Toruner M et al. Gastroenterology 2008

Mayo Clinic:

cases had IBD & opportunistic infections (n=100)

controls had IBD only (n=200)

Lichtenstein GR et al. Am J Gastroenterol 2014;109:212-23

SAFETY OF TREATMENTS

Osterman MT et al. Gastroenterology 2014;146:941-9


Risk of malignancies excluding NMSC

Risk of NMSC

Cottone M, et al. CGH 2011

Age is Risk Factor for Severe Infections and Mortalityin Patients Given anti-TNF alpha for IBD

95 elderly patients treated with biologics

190 adult matched controls treated with biologics

190 elderly controls not treated with biologics

UC CD UC CD UC CD

Pts n° 37 58 74 116 74 116

Male/female 20/17 35/23 40/34 70/46 40/34 70/46

Mean age(range) 71 (65-81) 71(65-84) 38(17-64) 39(16-64) 71(65-81) 70(65-80)

Remission n° (%) 22 (59.5) 38 (65.5) 42(56.7) 68 (58.6) - -

Maintenance n° (%) 12 (32.4) 39 (67.2) 24 (32.4) 78 (67.2) - -

Comorbidity n° (%) 35(94.5%) 44 (75.8) 4 (5.4) 6 (5.1) 37 (50) 46(39.6)

Deaths (n°) 4 6 0 2 2 3

Severe infections (n°) 5 6 2 3 1 0

Cancer (n°) 1 1 0 0 1 3

Steroids (n°) 36 54 72 108 74 104

Association antiTNF+AZA/6MP/MTX n(%)

7 (19) 15 (26) 17 (23) 32 (28) - -

10%

11%13%11% 2%

1% 2%

Efficacy and Safety of Anti-TNF Therapy in ElderlyPatients with IBD

(Univariable Analysis)

The rate of adverse events is higher in elderly pts but especially in those with a higher comorbidityCCI: Charlson Comorbiity Index

Ortega TL et al. Mo 1179; DDW 2014

In the multivariable analysis age remained an independent risk factor for severe infection [4,2; (1.2-14-4), p= 0.025] and SAE [2; (1.1-3.7), p= 0.029]

Age > 65 and CCI > 0 were risk factors for malignancy and mortality

Osterman MT et al. Gastroenterology 2014;146:941-9


Risk of malignancies excluding NMSC

Risk of NMSC

Risk of wrong prescriptions and the over treatment of biologics

CASE REPORTA 56-year old man presented tfor severe anemia (hemoglobin 6.7 g/dl) in absence of any sign of gastrointestinal bleeding but positive fecal occult blood test. He had not any previous diagnosis of CD and he was admitted to hospital. GI endoscopy that was normal. Ileocolonoscopy showed blood in the terminal ileum and only some small ulcers in the terminal ileum. Subsequently patient underwent to another ileo-colonoscopy that confirmed previous result. The histopathological examination of the ileal biopsies was compatible to CD diagnosis, confirmed by two pathologists. An MRI enterography was performed and showed increased bowel wall thickness in some ileal loops, narrowed lumen and dilatation confirmed by 2 abdominal CT, MRI and CT showed also multiple increased mesenteric lymph nodes (2-2.5 cm). Crohn’s disease was diagnosed on the basis of MRI enterography and patients began treatment with prednisone 1 mg/kg with no benefit.After 1 month, patient with severe abdominal pain, vomit, fever, persistence of severe anemia and melena. A double-ballon enteroscopy was performed but it was incomplete due to trouble in to pass terminal ileum. Given previous findings compatible with Crohn’s disease diagnosis but no response to corticosteroids treatment and the persistence of severe anemia refractory to iron therapy patient underwent surgery.

CASE REPORTA 56-year old man presented tfor severe anemia (hemoglobin 6.7 g/dl) in absence of any sign of gastrointestinal bleeding but positive fecal occult blood test. He had not any previous diagnosis of CD and he was admitted to hospital. GI endoscopy that was normal. Ileocolonoscopy showed blood in the terminal ileum and only some small ulcers in the terminal ileum. Subsequently patient underwent to another ileo-colonoscopy that confirmed previous result. The histopathological examination of the ileal biopsies was compatible to CD diagnosis, confirmed by two pathologists. An MRI enterography was performed and showed increased bowel wall thickness in some ileal loops, narrowed lumen and dilatation confirmed by 2 abdominal CT, MRI and CT showed also multiple increased mesenteric lymph nodes (2-2.5 cm). Crohn’s disease was diagnosed on the basis of MRI enterography and patients began treatment with prednisone 1 mg/kg with no benefit.After 1 month, patient with severe abdominal pain, vomit, fever, persistence of severe anemia and melena. A double-ballon enteroscopy was performed but it was incomplete due to trouble in to pass terminal ileum. Given previous findings compatible with Crohn’s disease diagnosis but no response to corticosteroids treatment and the persistence of severe anemia refractory to iron therapy patient underwent surgery.

adenocarcinoma moderately differentiated infiltrating the

muscular layer and the serosa layer and metastasis of the

peritoneum

Moderate

Severe

Conventional step-care

Accelerated step-care

Early top down

Conventional and evolving treatment strategy

Corticosteroids

IMS + TNF

antagonist

Corticosteroids +IMS

Corticosteroids +IMS

IMS + TNF

antagonist

IMS + TNF

antagonist

1998 2015…

Natural course of disease

A theoretical model: early, sustainable efficacy may have the greatest impact on clinical course

Adapted from Jones J, Panaccione R. Curr Opinion Gastroenterol 2008;24:475–81

Time

Dis

abil

ity

Disease onset

2015-16.. onwardsTreatment

at diagnosis

1998–2007Later

treatment

Intervention at diagnosis

Later intervention

S U S T A I N A B L E

2008-2014Earlier

treatment

Conclusions• Anti-TNFs are active long term maintenance therapies in IBD

• Effective interventions with biologics should be initiated before bowel damage becomes irreversible

• Clinical parameters can be used to predict an unfavourable disease course and thus promply identify which patients are at higher risk of disease progression

• Combo therapy seems to be effective than either drug alone in patients with early disease, but new studies are needed

• Patients with disease duration ≤ 2 years are most likely to benefit from TNF antagonists

• Presence of biological normalization suggestive of absence of infraclinical inflammation seems to be associated with a greater clinical benefit

• Optimize dosing of drugs and give therapy long enough but if not efficacious discontinue

Know your patient

Examine your patient

Screen your patient

Teach your patient

Treat and monitor

your patient

Does your patient need biologics?

Detailed interview:

Ideally the medical

history should cover

• Infections (bacterial and fungal)

• TB/opportunistic infections

• History of VZV and HSV

infections

• Immunisation status for HBV

• Vaccination status

• History of travel in tropical area

(future plans to travel in this

area)

Education

La terapia con anti TNF alfa nella Malattia di Crohn - Gastrolearning®