Alessandro Armuzzi , Daniela Pugliese

IBD Unit

Complesso Integrato Columbus – Università Cattolica - Roma

La terapia con anti-TNF alfa nella Colite Ulcerosa

Giulio, Male, 45 years old.

December 2012 December 2012 Symptoms at onset:

• Bloody diarrhoea (5 BM per day, 1-2 BM overnight).

• Mild abdominal pain (cramping mainly in lower abdominal quadrants).

• No fever.

• Weight loss: 4 Kg.

No family history for IBD or colon cancer.

No smoking, no drugs, no alcohol.

No stressful life events before diagnosis.

Iron deficiency anemia:Iron deficiency anemia:• Hb 11.2 g/dl • MCV 78 fl• Serum ferritin 12 ng/ml • Serum iron 32 mcg/dl

Inflammatory activity:Inflammatory activity:• CRP 16.8 mg/L (nv <5)• ESR 62

Stool cultures and stool ova and parasites tests: negative. Clostridium Difficile toxin: negative.

Colonoscopy: Colonoscopy: erythema, absence of vascular pattern, bleeding to light touch and erosions in rectum and in sigmoid colon, oedema in descending colon. Proximal to splenic flexure appeared normal up to the cecum.

Histology:Histology: acute and chronic inflammatory infiltrate in lamina propria, glandular distorption, severe cryptitis, cryptic abscesses (in both colon and rectum). No granulomas. No dysplasia.

MODERATE-SEVERE LEFT-SIDED ULCERATIVE MODERATE-SEVERE LEFT-SIDED ULCERATIVE COLITISCOLITIS

• Oral prednisone (50 mg/day, then tapered)• Mesalazine enema• Oral Mesalazine 2.4 gr/day

ACHIEVED CLINICAL RESPONSE ACHIEVED CLINICAL RESPONSE

Mesalazine 2.4 gr as maintenance therapyMesalazine 2.4 gr as maintenance therapy

Symptoms: Symptoms: bloody diarrhoea (5-6 BM per day, 1-2 BM overnight), tenesmusModerate abdominal pain (cramping mainly in lower abdominal quadrants).

Labs: Labs: CRP 30 mg/L (nv <5)ESR 62 Iron deficiency anemia (Hb 9.8 g/dl)

COLONOSCOPY: COLONOSCOPY: Severe inflammation with ulcers and erosions until hepatic flexure, normal ascending colon. Normal ileum. Mayo endoscopic score 3.

He started:

– New course of steroids: oral prednisone (50 mg/day)– Mesalazine enema– Oral Mesalazine 2.4 gr/day

Persistent bloody diarrhea (4 BM/day) and moderate Persistent bloody diarrhea (4 BM/day) and moderate abdominal pain after 14 days of 50 mg prednisoneabdominal pain after 14 days of 50 mg prednisone

He was defined as ORAL STEROID REFRACTORY!He was defined as ORAL STEROID REFRACTORY!

Ulcerative Colitis: increasing occurrence

Molodecky NA et al, Gastroenterology 2012

60% of UC studies have an increasing incidence of statistical

significance (P < 0.05)

The global map of UCCombined incidence & prevalence

Temporal trends of incidence rates

Worldwide UC incidence ratesand/or prevalence for countries reporting

data after 1980

Natural course of UC

Langholtz E, et al. Gastroenterology 1994

24

100

80

60

40

20

0

Years after diagnosis

Colectomy

Activity

Remission

0 2 4 6 8 10 12 14 16 18 20 22

% o

f p

atie

nts

UC disease activity over first 10 years

Solberg IC, et al. Scan J Gastroenterol. 2009

Norwegian IBSEN cohort study (1990–1994)

100Years

1%

6%

37%

55%

Ulcerative colitis (n=423)

Impact of chronic disease on daily life

Rubin DT, et al. Dig Dis Sci. 2010

*p<0.05 vs other chronic conditions

Rheumatoid arthritis(n=309)

Migraine (n=305)

Asthma (n=305)

UC (n=451)

Proportion of patients (%)

Patients who felt their condition was controlling their lives:

0

44

37

19

53 *

20 40 60

Online survey of adult patients in the US

Colectomy in ulcerative colitis over first 10 years

Solberg IC, et al. Scan J Gastroenterol. 2009;44:431–440.

Norwegian IBSEN cohort study (1990–1994) – n=519

9.8(95%CI 7.4-12.4)

19(95%CI 12-27)

8(95%CI 4-12)

5(95%CI 2-9)

Colectomy in UC: surgery rates in 35,782 patientsNationwide Danish cohort study 1979–2011

Rungoe C, et al. Gut 2014;63:1607–16

Cohort I (1979–86)

Cohort II (1987–94)

Cohort III (1995–02)

Cohort IV (2003–11)

p<0.001

14.5%

9.1%

Colectomy rates in UC

025

Time since diagnosis (years)

20

40

60

80

20151050

Cohort IVCohort IIICohort IICohort I

020

Time since diagnosis (years)

20

40

60

80

151050

Cohort III + IV

020

Time since diagnosis (years)

20

40

60

80

151050

Cohort III + IV

Current use of AZA

Never use AZA

Never use oral corticosteroids

Current use of corticosteroids

Cumulative probability of surgery in UC

Risk matrix model for prediction of colectomyThe IBSEN cohort

•Population-based study of 464 UC patients•10-year FU/45 colectomy•Multiple regression to selected risk factors fitted into a prediction model

ESR

Under 30 Over 30

Age at diagnosis

< 40 years 8.0%(5.5-10.5)

29.9%(25.8-34.1)

Yes Systemic steroids

at diagnosis> 40 years 2.3%

(1.0-3.7)10.5%

(7.7-13.5)No

E1-E2 E3

Extent of disease at diagnosis

Cvancarova M, et al. Gut 2010

Risk is 15 times higher in young patients, with E3,ESR>30 and who need CS at diagnosis

Definitions, management: consensus guidelines

JCC 2010, 2012, 2013, 2014; DLD 2011; Autoimm Rev 2014

According to:

- Disease activity

- Disease extension

- Disease course pattern

- Previous treatments

- Biologic/endoscopic signs

of inflammation

- EIMs

- Potential for complications

- Patient’s expectation

Medical management of active ulcerative colitis

General Principles

Anti-TNF alpha in moderate-to-severe, severe UC

Personal perception

1. Several trials have investigated the efficacy of anti-TNFs for moderate, moderate to severe and severe UC

2. In most trials, anti-TNFs were more effective than placebo and, generally, they were found to be well tolerated

3. However, anti-TNFs place in the treatment algorithms for UC still remains to be clearly defined

Benefits of anti-TNF therapy in UCevidence from clinical trials (IFX, ADA, GLM)

1. Reinisch W, et al. Gut 2011;60:780–7;2. Sandborn W, et al. Gastroenterology 2012;142:257–265;3. Rutgeerts P, et al. N Engl J Med 2005;353:2462–76; 4. Sandborn W, et al. Gastroenterology 2014;146:85–95 and 96–109;5. Sandborn WJ, et al. Aliment Pharmacol Ther 2013;37:204–13;6. Sandborn WJ, et al. Gastroenterology 2009;137:1250–60;

7. Feagan BG, et al. Gastroenterology 2014;146:110–8;8. Reinisch W, et al. Am J Gastroenterol 2010;105(Suppl. 1):S441;9. Feagan BG, et al. Am J Gastroenterol 2007;102:794–802; 10. Feagan B, et al, J Crohns Colitis 2013;7(suppl 1):S99–100;11. Wolf D, et al. Aliment Pharmacol Ther 2014;40:486–97;12. Colombel J-F, et al. Am J Gastroenterol 2014;109:1771–80

Goal Benefit Study

Response ULTRA 11, ULTRA 22, ACT 1&23, PURSUIT4

Remission ULTRA 11, ULTRA 22, ACT 1&23, PURSUIT4

Steroid-free remission ACT 1&23, ULTRA 25

Mucosal healing ULTRA 22,5, ACT 1&23,6, PURSUIT4

Reductionin hospitalisation ACT 1&26, ULTRA 1&27

Reduction in surgeries ACT 1&26, ULTRA 1&27

Improved QoL ULTRA 18, ACT 1&29, PURSUIT10

Dose flexibility ULTRA 2 (1y)11

Sustained efficacy ULTRA 2 (1y)2,5, ACT 1 (1y)3, PURSUIT (1y)4, ULTRA 1,2,3 (4y)12

≈/<1/3at 1 yr

Patients enrolled in randomised controlled trials do not represent the IBD patient population

Clinical trials Clinical practice

Defined population Heterogeneous population

Prescribed treatment regimen

Variable treatment regimen with optimisation

Follow-up regimented with schedule

Follow-up not fixed

Uniform primary end-point Variable outcomes

Efficacy Effectiveness

The IBD population: clinical trial versus clinical practice

31% of patients were not eligible for participationin a clinical trial of biologic therapy*

Ha C, et al. Clin Gastroenterol Hepatol 2012;10(9):1002-7

*Inclusion criteria based on those published for 9 trials of biologic therapy: ACCENT I, CLASSIC I, CHARM, PRECISE I, ENCORE, ENACT, SONIC, ACT 1, ACT 2

Retrospective study of patients with moderate-severe IBD at a US tertiary referral centre (n=206)

Reasons for exclusion in CD

●Strictures or abscesses (62%)

●Recent exposure or nonresponse to anti-TNF (51%)

●High-dose steroids (18%)

●Comorbidities (26%)

Reasons for exclusion in UC

●Current rectal therapy use (57%)

●Steroid and immunomodulator naïve (45%)

●Newly diagnosed (17%)

●Colectomy likely (15%)

The “unusual” history of TNF antagonist use in IBD

• 2000: monotherapy, intermittent use

• 2003-05: combination therapy

• 2006-9 : opportunistic infectionsHSTCLsubgroup and post-hoc analyses:

the “flight” to monotherapy

• 2010: combination therapy in the naïve CD patient, early treatment in CD, exit strategies

• 2013-2014: combination therapy in the naïve UC patient, postoperative recurrence in CD, TDM

Translating results from clinical trials into real life: tailored management of UC patients in my practice

● Establish shared goals with the patient(with understanding of patients’ unmet needs)

● Categorise the patient(with understanding of disease clinical characteristics and prognosis)

● Set up the management plan(appropriate initial therapy with monitoring and timely adaptation)

Physician–patient shared goals in UC

Typical physician goals, with long-term perspective

●Induce (clinical + endoscopic) remission

●Maintain (clinical + endoscopic + histologic) steroid-free remission

●Prevent complications (disease and therapy-related)

●Optimise timing of surgery, when needed

Typical patient goals, with short-term perspective

●Minimise symptoms, fast relief

●Steroid avoidance

●Sustained symptom relief

●Colectomy avoidance

●Minimise side-effects of medications

●Have the opportunity to discuss fears/anxieties/uncertainties and related issues with physician

UC patients categorisation in clinical practice

Patients responding to 5-ASA or steroids and with sustained remission under 5-ASA

or thiopurines

Patients with occasional flares on 5-ASA or thiopurines

Patients with steroid-dependent disease (flares on tapering or stopping steroids)

Patients with oral steroid-refractory disease

Candidates for colectomy

Patients with chronically active disease

(not completely controlled with ‘standard’ therapy)

Patients with acute severe disease

Ulcerative colitis: tailored and timely bottom up

Management plan

AminosalicylatesAminosalicylates

SurgerySurgery

IFX / CyAIFX / CyA

IV corticosteroidsIV corticosteroids

Mild

Severe

Moderate

Fulminant

Oral corticosteroids/AZAOral corticosteroids/AZAAnti-TNF-α

Acute severe UC - Treatment goals

• Avoid mortality

• Avoid colectomy

• Reduce hospital stay and drug-related AEs

1) hospital admission for intensive treatment

Acute severe UC

Acute Severe UC mortality

100%

0%

50%

1950 1965 1975 2010

I.v. steroidsOxford schedule

5-days regimenEarly colectomy policy New drugs

CyA, IFX

“5 days regimen”

Inpatient

iv Prednisolone or hydrocortisone

Topical enemas

Electrolytes

Plasma blood

Antibiotics

Low molecular weight heparin

Truelove & Jewell, 1974-1978

Therapy of acute severe UCAcute severe UC

Acute severe UC

32 studies from 1974 to 2006 (1991 patients)

response to steroids 67% (95% CI 65–69%)colectomy rate 29% (95% CI 28–31%) mortality 1% (95% CI 0.7–1.6%)

• Colectomy rate did not change during the last 30 yrs (R2 0.07, p=0.8)

• No dose-colectomy response of mpred beyond 60 mg (R2 <0.01, P 0.98)

Turner D, Clinical Gastroenterol Hepatol 2007

Corticosteroids in severe active UC

Cyclosporin vs infliximab in acute, severe, i.v. refractory UC

Laharie D, et al. Lancet 2012;380:1909–15

● Lichtiger score >10 after at least 5 daysof i.v. Methyl PDN (0.8 mg/kg/d)

● 116 patients

● Primary endpoint: treatment failure based on 6 criteria (no response D7;no CS-free remission D98; relapse between D7-98; ASE; colectomy; death)

● 55 patients: Cys (2 mg/kg/d for 1 week, then oral)

● 56 patients: IFX (5 mg/kg at 0, 2, 6 weeks)

● If D7 response: AZA 2.5 mg/kg/d and steroid tapering

Severe i.v. steroid-refractory UC

Previous thiopurine failure/intolerance

IFX 5 mg/Kg, 0-2-6 wks i.v. Cyclosporine 2 mg/Kg or

IFX 5 mg/Kg, 0-2-6 wks

Steroid tapering; start thiopurines (naïves);Switch to oral cyclosporine or IFX maintenance;Consider a bridging strategy in thiopurine-naïve

Colectomy

yes no

Clinical assessment at day 5-7 by medical/surgical team

response ?

Exclude toxic megacolon

3-5 days

5-7 days

yes no

IV steroid -refractory UC

Cumulative probability of a colectomy-free coursewithin 5 years from IFX rescue therapy in ASUC

Monterubbianesi R, et al. JCC 2014;

73.9% 69.2% 66.1%

60%

37 of 113 patients required colectomy during follow-up(overall colectomy rate 32.7%; 95 CI 24.2% to 42.2%)

Variable RR 95%CI P

Gender (male)

1.020.52 to

1.990.9

Age<40 yrs 1.12 0.56 to 2.20 0.7

CRP>3 mg/dl 2.151.05 to

4.360.03

Severe EL 5.131.55 to 16.96

0.007

1.Sandborn WJ et al. Gastroenterology. 2009;137:1250 1260. ‒2. Ferrante M et al. J Crohns Colitis. 2008;2:219–225. 3. Oussalah A et al. Am J Gastroenterol. 2010;105:2617–2625.4. Reinisch W et al. Gut. 2011;60:780–787. 5. Armuzzi A et al. Inflamm Bowel Dis. 2013;19:1065–1072. 6. Armuzzi A et al. Dig Liver Dis. 2013;45(9):738-4.7. Sandborn WJ et al. Aliment Pharmacol Ther. 2013;7:204 213. ‒

Factors associated with colectomy or lower rates of clinical remission in UC outpatients treated with anti-TNFColectomy

● Mayo score ≥101

● Mayo endoscopic score ≥2 after induction1,9,11

● High baseline CRP1,2,3,11

● Steroid dependency1

● UC with duration ≥2/3 years1,11

● No response after induction2,3

● Previous rescue therapy2,3

● High CRP after induction10

● Mayo endoscopic score >2 at baseline10

● Prior anti-TNF treatment13

Low rates of clinical remission

● Mayo score ≥104

● Mayo endoscopic score ≥2 after induction1,11

● CS + IM at baseline4

● High baseline CRP4

● High CRP after induction5,6, 10, 11

● Late response (>8–12 weeks)6,7

● Immunosuppressor experienced6

● Anti-TNF monotherapy5,8,10

● Prior anti-TNF treatment12,13

8. Panaccione R et al. Gastroenterology 2014;146:392–400. 9. Laharie D et al. Aliment Pharmacol Ther. 2013;37:998 1004; ‒10. Armuzzi A, et al. Inflamm Bowel Dis 2014;20:1368–74; 11. Arias MT, et al. CGH 2014; epub ahead of print; 12. Wolf D, et al. Aliment Pharmacol Ther 2014;40:486–97; 13. Iborra M, et al. ECCO 2015:P303.

Moderate-severe UC

Long-term outcome after IFX/ADA in refractory or steroid-

dependent UC

Armuzzi A , et al. Inflamm Bowel Dis 2014

Predictor of sustained clinical response:-IFX + AZA

(HR 3.98, 95%CI 1.7-9.1, p<0.001)

Rome/Milan - N = 126 UCmedian FU 42 months (IQR 26-65)

64.5% sustained clinical response at median FU

Italy - N = 88 UCmedian FU 13 months (IQR 6-21)

0 10 20 30 40 50 60

100

90

80

70

60

50

40

30

20

10

0

Time (months)

Sur

viva

l pro

babi

lity

(%)

Number at risk88 61 23 8 3 1 1

65.9 %

Predictor of 12-month clinical remission:-Week 12 remission

(OR 4.25, 95%CI 1.2-14.4, p=0.02)-Normal CRP at 12 weeks

(OR 5.19, 95%CI 1.7-16.1, p=0.004)

Armuzzi A et al. Dig Liver Dis 2013

Moderate-severe UC

Colectomy-free survival with long-term anti-TNFs in UC

0 10 20 30 40 50 60

100

90

80

70

60

50

40

30

20

10

0

Time (months)S

urvi

val p

roba

bilit

y (%

)

Number at risk88 71 33 12 5 2 1

79 %

Armuzzi A et al. Dig Liver Dis 2013;45:738-43

77 %

N = 126 UC - IFXmedian FU 42 months (IQR 26-65)

Armuzzi A , et al. Inflamm Bowel Dis 2014

N = 88 UC - ADAmedian FU 15 months (IQR 12-23)

Predictors of colectomy:

High CRP after induction - OR 5.65 (95%CI 2.02-15.7)Endo Mayo baseline=3 - OR 2.76 (1.08-7.05)

Moderate-severe UC

Impact of MH on long-term outcomes in UC treated with infliximab

Colectomy-free survival according to endoscopic response

Arias MT, et al. Clin gastroenterol Hepatol 2014

Relapse-free survival according to endoscopic response

Moderate-severe UC

A Panel to Predict Long-term Outcome of Infliximab Therapy for Patients with Ulcerative Colitis

Arias MT, et al. Clin gastroenterol Hepatol 2014

Predictive factors of relapse-free survival

Predictive factors of colectomy-free survival

Multivariate analysis (n=146)

OR (95% CI) P

Short-term clinical response

3.75 (2.35-5.97 <0.001

Short-term MH 1.87 (1.17-2.98) 0.009

pANCA negative 1.96 (1.23-3.12) 0.005

Multivariate analysis (n=195)

OR (95% CI) P

Short-term clinical response

7.74 (2.76-21.78) <0.001

Short-term MH 4.02 (1.16-13.97) 0.028

Baseline CRP≤5mg/ml

2.95 (1.26-6.89) 0.012

Baseline albumin ≥35g/L

3.03 (1.12-8.22) 0.029

P<0.001

P<0.001

Non-response to anti-TNF alpha and management

Hanauer SB, et al. Lancet 2002; Rutgeerts P, et al.NEJM 2005; Hanauer SB, et al. Gastroenterology 2006; Colombel JF, et al. Gastroenterology 2007; Rudolph SJ, Dig Dis Sci 2008; Afif W, et al. IBD 2009; Schnitzler F, et al. Gut 2009; Oussalah A, et al. AJG 2010; Kiss LS, et al.APT 2011; Reinisch W, et al.Gut 2011 ; Ben Horin S, et al. Autoimm Rev 2013; Gisbert JP, et al. AJG 2009; Billioud V, et al. AJG 2011

Primary: 20-40% in clinical trials (10-20% in 'real life'

series), no reliable predictors

Secondary: annual risk 13-20% per patient-year of follow

up, no reliable predictors

“Empirical” dose-escalation: 60% of response

TDM: useful in some situations, not routinely used

Shift “in-class”: possible, reduced rates of response

Shift “out-of-class”: possible, reduced rates response

Colectomy: benefit/risk balance

Proposed algorithm for moderate, moderate to severe UCPrevention and management of chronic active disease

FailureAZA

(12 weeks)Anti-TNF ± AZA

Prednisone

ModerateModerate-severe

Steroiddependent

SteroidrefractoryRespond and taper

5-ASA/AZA maintenance

flares onstopping steroids

flares ontapering steroids

Prompt identification Prompt identification

Clinical and endoscopicremission

Switch in class,

Switch out of class, or

surgery

Primary failure/LoR

115 CD patients in remission on IFX+AZA(CDAI<150 and steroid free ≥6 months)

Factor HR (95%CI) P

No previous surgery 4.0 (1.4-11.4) 0.01

Steroids (month -12 to -6) 3.5 (1.1-10.7) 0.03

Hemoglobin ≤ 14.5 (g/dl) 6.0 (2.2-16.5) <0.001

Male Gender 3.7 (1.9-7.4) <0.001

Fecal calpro ≥ 300 μg/g 2.5 (1.1-5.8) 0.04

Infliximab TL ≥ 2 mg/L 2.5 (1.1-5.4) 0.02

WBC > 6 (103/ml) 2.2 (1.2-4.2) 0.01

CRP hs > 5 (mg/l) 3.2 (1.6-6.4) <0.001

CDEIS > 0 2.3 (1.1-4.9) 0.04

Median follow up 28+/- 2 months

52.2% relapse43.9% relapse

Stopping rules for UC as in the STORI trial for CD?

Louis E, et al. Gastroenterology 2012;142:63–70

Prognostic Value of Histologic Markerson Clinical Relapse in UC Patients With MH

Bessissow T, et al. Am J Gastroenterol 2012;107:1684–92

75 UC patients with Mayo endo score =0 and 1-year FU

Factors OR (95% CI) P

Basal plasmacytosis 5.13 (1.32–19.99) 0.019

Biologics 0.24 (0.05–1.01) 0.052

Practical algorithm for UC on combination therapy

Consider to Stop anti-TNF and maintenance on AZA

Steroid-free remissionMucosal healing

Histological healingNormal CRP/Calpro

Anti-TNF + AZA

IMM naïve IMM refractory

Sustained “deep” remission

Goals to achieve

Consider to Stop AZA andmaintenance on anti-TNF

Sustained “deep” remission

YesYes

No

Risk/benefit assessmentTherapy escalation

ShiftSurgery