Gastrolearning II modulo/19a lezione La terapia con anti TNF alfa nella Malattia di Crohn Relatore: Dr. Ambrogio Orlando (Palermo)

1. La terapia con anti TNF alfa nella
Malattia di Crohn
Relatore: Dott. A. Orlando (Palermo)
LUNEDI 9 FEBBRAIO
ORE 15.30

2. 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 symptoms
and lesions (early)
with long term
strategy

3. 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 statements
234 reccomendations
(diagnosis & management)
47 statements
103 reccomendations
(anti TNFα therapy)
4. Guidelines
The majority of reccomendations
are based on expert opionions !

4. Crohn’s Disease is not a 6-week
diseases !
Lifelong management and strategies
are necessary

5. 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

6. 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

7. 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

8. 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

9. Definition of Outcomes
Luminal Crohn’s disease
Clinical response
CDAI reduction > 70 points from the baseline
CDAI reduction > 70 points + at least 25% reduction from the baseline
Clinical remission
CDAI < 150
Steroid sparing
Clinical remission (CDAI < 150) and off steroids
Mucosal healing
Mucosal ulceration at wk 0 and no mucosal ulceration at follow-up
Deep remission
Defined as clinical remission (CDAI <150) and complete MH

10. Orlando A. et al. Digestive and Liver Disease 2011; 43: 1–20
GOALS OF MANAGEMENT IN CROHN’S DISEASE

11. GOALS OF MANAGEMENT IN CROHN’S DISEASE

12. Orlando A. et al. Digestive and Liver Disease 2011; 43: 1–20
GOALS OF MANAGEMENT IN CROHN’S DISEASE

13. GOALS OF MANAGEMENT IN CROHN’S DISEASE
Annese V. et al. Journal of Crohn's and Colitis (2013) 7, 982–1018

14. GOALS OF MANAGEMENT IN IBD
Mary JY et al. Gut 1989;30:983-9Daperno M. et al. Gastrointest Endosc 2004;60:505-12

15. MUCOSAL HEALING IN CROHN’S DISEASE

16. Overview of the evolution of primary endpoints of CTs
in luminal CD
Hindryckx P et al JCC 2014 May

17. 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

18. 0
5
10
15
20
25
30
35
ACCENT I
51% steroids at entry
pla
CHARM
44% steroids at entry
pla
5mg/kg
10mg/kg
40mg eow
40mg weekly
STEROID SPARING EFFECT
(CORTICOSTEROID FREE REMISSION AT 1 YEAR)

19. 90 -
80 -
70 -
60 -
50 -
40 -
30 -
20 -
10 -
0 -
Response rate
Remission rate
Week 6
%patients
45.5%
100 -
45.5%
90 -
80 -
70 -
60 -
50 -
40 -
30 -
20 -
10 -
0 -
Response rate
Remission rate
%patients
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.

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

21. Response to anti-TNFs in Pivotal Trials
(All randomized patients)
Certolizumab
PRECISE 2
(400 mg/4Wk)
Infliximab
ACCENT 1
(5 mg/kg/8Wk)
Adalimumab
CHARM
(40 mg/2Wk)
Primary
Non Responders
Secondary
Non Responders
Longterm
Responders
∆100
Remission
∆70
Remission
∆70
∆100
Remission
%
64
40
29
0
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

22. 1)
2)
3)
smoking should be discouraged in all patients
Maintenance of medically induced remission guidelines

23. Evolving goals of therapy for Crohn’s disease:
“sustained steroid clinical free remission”
Response
Steroid free
Remission
Goal Clinical parameters
Improved symptoms
No symptoms
Normal labs
Outcomes
Improved QoL
Decreased
hospitalisation
SUSTAINED

24. 2
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

25. 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
Cumulativeprobabilityofremaining
freeofcomplications(%)
Inflammatory
Months
372,002 552 229 95n =
Patients at risk:
Start
therapy

26. 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

27. Longitudinal course of rheumatoid arthritis
Kirwan JR. J Rheumatol 2001
Disease duration (years)
Disability
Radiographs
Inflammation
Severity
(arbitraryunits)
0 5 10 15 20 25 30
Early RA Intermediate Late
Klareskog L, et al. Lancet 2009

28. 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
59,6
55,8
39
57
0
10
20
30
40
50
60
70
80
90
100
IFX ACCENT/REACH
wk 30 remission
IFX ACCENT/REACH
wk 54 remission
ADA CHARM/PED
wk 26 remission
%remission
Adult CD Ped CD
Disease duration: adult ~8 yr – pediatric ~2 yr

29. 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
Patientswithremission(%)
23n= 39
<2 years
17%
51%
36 57
2 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

30. IFX (0,2,6 wk)
AZA (2-2.5 mg/kg)
133 CD < 4 yrs duration
CDAI>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

31. 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 98104
Weeks after randomisation
Patientswithnorelapse(%)
//
Top down
Step up
Weeks from diagnosis to treatment
2.0 (1–5) - 2.5 (1–11)

32. Early treatment in Crohn’s disease
Orlando A et al. Dig Liver Dis. 2011; 43:1-20
Van Assche G et al JCC 2010

33. 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
Concomitant
Immunomodulators
No concomitant
Immunomodulators
ODDS RATIO FOR RESPONSE/REMISSION IN PATIENTS WITH AND
WITHOUT CONCOMITANT IMMUNOMODULATORS
Subgroup 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

34. Karmiris K, et al. Gastroenterology 2009
Anti-TNF alpha and concomitant IM (Leuven)
Schnitzler F, et al. Gut 2009
IFX ADA

35. • > 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

36. To combine or not to combine ?
Van Assche G et al JCC 2010 Orlando A et al. Dig Liver Dis. 2011; 43:1-20

37. All patients: 854
Patients treated with corticosteroids at baseline: 376 (44%)
Colombel et al. Gastroenterology 2007;132:52-65

38. Up to 4 years!!
Panaccione R et al Aliment Pharmacol Ther 2013
Long-Term Maintenance of Clinical Remission
(ADHERE)

39. 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.

40. 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
Patients(%)
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!!

41. Results
Long Term Adalimumab Efficacy In Steroid-dependent
Crohn’s Disease Patients
Univariable analysis
p-value OR (95% CI)
Induction dosage vs maintaining clinical remission p = 0.06 2.01 (0.944-4.266)

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

44. 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);

45. 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

46. BIOLOGICS IN CROHN’S DISEASE
Anti-TNFα antibodies vs. placebo in healing of fistulizing CD
Ford et al. Am J Gastroenterol. 2011;106:644-59

47. 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)
%pazienti
(n=195) (175 fistole perianali)
Malattia perianale – Terapia con anti-TNF
 Ascesso perianale nel 12% dei pazienti trattati con Infliximab

48. 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 remission
at 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

49. Biological immunomodulators improve the healing rate in
surgically treated perianal Crohn’s fistulas
(Cleveland Clinic)
El Gazzaz G et al. Colorectal Disease 2012; 14: 1217-
218 CD patients with
active perianal
fistulusing disease.
Group A:
surgery 54 %
Group B:
surgery+biologics 46%
Mean Follow-up 3.2 ys

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

51. MUCOSAL HEALING AND ANTI-TNFα
Beppu T. et al. Digestive Endoscopy 2015; 27: 73–81

52. Rutgeerts P et al. Gastroenterology 2012;142:1102-
MUCOSAL HEALING AND ANTI-TNFα
 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

53. Colombel JG et al. N Engl J Med 2010;362:1383-95
MUCOSAL HEALING AND ANTI-TNFα

54. 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

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

56. Schnitzler F et al. Inflamm Bowel Dis 2009;15:1295–1

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

58. SHADOWS ON MUCOSAL HEALING

59. Rutgeerts P et al. Gastrointest Endosc 2006;63:433-42
MUCOSAL HEALING AND ANTI-TNFα
?

60. Björkesten CG, Inflamm Bowel Dis. 2011;17:947-53
MUCOSAL HEALING AND ANTI-TNFα
?

61. Bouguen G et al. Clin Gastroenterol Hepatol 2014;12:978-85
MUCOSAL HEALING AND ANTI-TNFα
?

62. Solberg IC, et al. Clin Gastroenterol Hepatol 2007;5:1430–8
IBSEN: disease course in Crohn’s disease over 10 years
Diseaseactivity
0 1010Years 0 Years
43% 19%
3% 32%
Missing data, 3%
However… Management Must Be Tailored to the
Individual Patient

63. Disease severity Patient’s expectation
Benefit / risk of treatment
Patient’s preference
Patient Selection:
Tailored

64. • 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

65. 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

67. CLINICAL PRACTICE
CLINICALCLINICAL
RESEARCHRESEARCH
(Sample Size)(Sample Size)
Different
drug
dosages
Length
of
therapy
Age
limit
Concomitant
therapy
not permitted
in the trials
Concomitant pathologies
Alterated organ function
DIVARICATION BETWEEN CLINICAL RESEARCH AND CLINICAL PRACTICE
Referral centres with different experience

68. Comorbidities
Malnutrition,
Disease
severity,
Surgery
Underlying
disease
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: 929-936
2. 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 to
pathogens
Immunomodulator
therapy
Geographic
clustering
Piogenic infections
(Pneumonia, TBC,
urinary tract infections)
Viral infections
Immunomodulator therapy
Viral infections may occur with anti-TNFs, viruses are
more prominent with the thiopurines

69. 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)

70. Lichtenstein GR et al. Am J Gastroenterol 2014;109:212-2
SAFETY OF TREATMENTS

71. Osterman MT et al. Gastroenterology 2014;146:941-9
SAFETY OF TREATMENTS
Risk of malignancies excluding NMSC
Risk of NMSC

72. Cottone M, et al. CGH 2011
Age is Risk Factor for Severe Infections and Mortality
in 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%

73. Efficacy and Safety of Anti-TNF Therapy in Elderly
Patients with IBD
(Univariable Analysis)
The rate of adverse events is higher in elderly pts but especially in those with a higher comorbidity
CCI: 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

74. Osterman MT et al. Gastroenterology 2014;146:941-9
SAFETY OF TREATMENTS
Risk of malignancies excluding NMSC
Risk of NMSC

75. Risk of wrong prescriptions and the over
treatment of biologics

76. CASE REPORT
A 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.

77. adenocarcinoma moderately
differentiated infiltrating the
muscular layer and the serosa
layer and metastasis of the
peritoneum

81. 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…

82. 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
Disability
Disease onset
2015-16.. onwards
Treatment
at diagnosis
1998–2007
Later
treatment
Intervention at diagnosis
Later intervention
S U S T A I N A B L E
2008-2014
Earlier
treatment

83. 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

84. 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)