Update on IBD

Raymond K Cross, MD, MS University of Maryland

Baltimore, MD

Disclosure

• Grants/Research Support: AbbVie,

Janssen, Shire

• Consultants/Speaker Bureau: AbbVie,

Janssen, Takeda

• Honorarium Recipient: AbbVie, Janssen,

Takeda

Agenda

• Laboratory markers in IBD:

Useful or unnecessary?

• Deep remission: What does it mean and

how do we achieve it?

• Managing biologics: First- and second-line

treatment options

Case Study

• A 30-year-old male presented with

progressive symptoms of bloody

diarrhea over 3 weeks

• Prescribed ciprofloxacin by internist

with the presumption that the diarrhea

was infectious

– Stool cultures for pathogens were

negative; symptoms persisted despite

5 days of antibiotic

• The primary care provider (PCP)

ordered serologic tests

– Before results were available he

underwent a colonoscopy that

demonstrated severe colitis extending

to 40 cm

– The ileocecal valve was normal but

there was a patch of superficial

inflammation around the appendix

Case Study

• Biopsies from left colon demonstrated severe

colitis with ulcerations, crypt abscesses,

architectural distortion but no granulomas

• Intervening mucosa and ileum were normal

• Crypt abscesses and mild architectural distortion

present in the periappendiceal biopsies

How might serologic markers be useful in the

management of this patient?

Case Study

• The patient was treated with prednisone

and had complete relief of his symptoms

over the ensuing 6 weeks

• He was transitioned to mesalamine

4.8 g/day

• A fecal calprotectin was measured and

was 350 mcg/g

How would you react to this calprotectin result?

Fecal Biomarkers of Inflammation

• Calprotectin1,2

– Granulocyte cytosolic protein

– Stable in feces for days

• Lactoferrin1,2

– Neutrophil granule protein

– Stable in feces

Considerations:

• Elevated in NSAID enteropathy, cancer, celiac disease,

microscopic colitis

• Sensitivity and specificity vary greatly based on cutoff value

NSAID=non-steroidal anti-inflammatory drug

1. Vermiere S et al. Gut. 2006;55:426-431; 2. Montalto M et al. Eur Rev Med Pharmacol Sci. 2013;17:1569-1582.

C-Reactive Protein

• Acute-phase protein

• Produced in liver under influence of IL-6/

TNF-alpha/IL-1β

• Short half-life (~19 hours)

Considerations:

• May be more elevated in CD than in UC

• Elevated in other conditions (eg, infections, obesity,

• coronary artery disease)

• Patients with ileal disease or low BMI may have low CRP

even in active disease

• 10% to 40% have no or minimal CRP response

• CRP production may be influenced by genetic polymorphisms

BMI=Body Mass Index; CRP=C-reactive Protein; IL=Interleukin; TNF=Tumor Necrosis Factor

Vermeire S et al Gut.2006;55:426-431.

Erythrocyte Sedimentation Rate

• Defined as the rate RBCs settle in 1 hour

Considerations:

• Influenced by anemia, gender, pregnancy

• Peaks less rapidly than CRP

• Resolves more slowly than CRP

CRP=C-reactive protein; RBC=Red Blood Cell

Vermeire S, et al Gut.2006;55:426-431.

Calprotectin: Utility in Differentiating

IBS from IBD

FC=Fecal Calprotectin; IBS=Irritable Bowel Syndrome

Keohane J, et al. Am J Gastroenterol. 2010;105:1789-1794.

FC levels in patients with CD with and without

IBS-like symptoms

Controls IBS

Ca

lpro

tecti

n (

mg

/kg

sto

ol)

0

25

50

125

100

150

175

200

75

FC levels in IBS Patients vs

Healthy Volunteers

Fecal Calprotectin Correlates

With Disease Activity

De Vos M et al. ECCO 2012. Abstract No. OP 07.

• UC patients in remission on infliximab 5 mg/kg

q8 weeks (n=113)

- Fecal calprotectin measured monthly for 1 year

- Deep remission = normal endoscopy at baseline and week 52 +

Mayo score

Biomarkers Correlate Well With Endoscopic

But Not Clinical Activity Indices

CDAI=Crohn’s Disease Activity Index; CRP=C-reactive Protein; IL=Interleukin

Jones JL et al. Clin Gastroenterol Hepatol. 2008;6:1218-1224.

Correlation coefficients in blue were significant (P

Correlation Between Symptoms, Biomarkers,

and Endoscopic Disease Activity

CDAI=Crohn’s Disease Activity Index; CDEIS=Crohn’s Disease Endoscopic Index of Severity; CRP=C-reactive Protein;

FCP=Fecal Calprotectin; FL=Fecal Lactoferrin; PPV = Positive Predictive Value; NPV=Negative Predictive Value

Sipponen T, et al. Inflamm Bowel Dis. 2008;14:40-46.

Measure Sensitivity Specificity PPV NPV

CDAI >150 27% 94% 91% 40%

CRP >5 mg/L 48% 91% 91% 48%

FCP >200 mcg/g 70% 92% 94% 61%

FL >10 mcg/g 66% 92% 94% 59%

Prognosis: High Fecal Calprotectin is

Associated with Risk of Relapse in IBD

Tibble JA, et al. Gastroenterology. 2000;119:15-22.

RR 10.6 (CD)

RR 13.4 (UC)

43 CD

37 UC

In remission for 1-4 months

25 (58%) relapsed over period of 12 months

19 (51%) relapsed over period of 12 months

Proportion of patients without a relapse

Time (months)

UC calprotectin 50 mg/L

CD calprotectin 50 mg/L

3 6 9 12 0

1

0

Value of CRP in Predicting CD Relapse

CRP=C-reactive Protein

1. Oussalah A, et al. Am J Gastroenterol. 2010;105:1142-1149; 2. Papi C et al. 2007;102:814-819; 3. Louis E, et al. DDW 2012.

Time (days)

Su

rviv

al

pro

bab

ilit

y w

ith

ou

t

infl

ixim

ab

fa

ilu

re (

%)

0 200 400 600 800 1000

CRP510

20

30

40

50

60

70

80

90

100

Time (months)

CRP5

0 2 4 6 8 10 12

P=0.030

20

40

60

80

100A

%

Infliximab failure after

azathioprine withdrawal in CD

treated with combination therapy1

Cumulative probability of

steroid-free course after

steroid-induced remission by

CRP value at steroid weaning2

In patients on infliximab, a spike in CRP to 8 mg/dL

predicted clinical relapse within 4 months3

Fecal Calprotectin Predicts Outcome After

Induction Therapy With TNF Antagonists

• Patients

– 60 IBD patients

(CD, n=34; UC, n=26)

– Treated with TNF antagonists

– Documented FC concentration

at baseline and after induction

therapy

• Results

– FC normalized (≤100 mcg/g) in 31

patients (52%)

– At ~12 months, 84% of patients

with normal FC after induction

were in clinical remission vs 38%

of those with elevated post-

induction FC

0

20

40

60

80

100

Normal FC AfterInduction

ElevatedPostinduction FC

*Remission defined as a Harvey-Bradshaw Index

Agenda

• Laboratory markers in IBD: Useful

or unnecessary?

• Deep remission: What does it mean and

how do we achieve it?

• Managing biologics: First- and second-line

treatment options

Case Study (Continued)

• A flexible sigmoidoscopy was performed

despite the patient feeling well

• The scope revealed an intact mucosa in the

rectum but there were:

– Residual inflammatory changes of mucosal erythema

– Loss of vascularity in the sigmoid colon

– Superficial erosions in the sigmoid colon

Case Study (Continued)

• Biopsies demonstrated an increased

inflammatory infiltrate with a few crypt

abscesses and architectural distortion in the

rectum

• Biopsies from the sigmoid demonstrated a more

intense inflammatory infiltrate with

superficial ulcerations

What is the patient’s prognosis?

How should he be managed?

Definitions of Remission in IBD

CDAI=Crohn’s Disease Activity Index; CDEIS=Crohn’s Disease Endoscopic Index of Severity; CRP=C-reactive Protein;

HBI=Harvey-Bradshaw Index; SES=Simple Endoscopic Score; UCDAI=Ulcerative Colitis Disease Activity Index

Modigliani R, et al. Gastroenterology. 1990;98:811-817.

Ulcerative Colitis Crohn’s Disease

Clinical remission CDAI score ≤4

Lichtiger Index score ≤3

CDAI

Clinical Predictors of Complicated

Clinical Course in Crohn’s Disease

aDisabling CD: steroid dependence, repeat hospitalization after diagnosis, 12 months of “disabling symptoms”, need for IS, resection, or operation for

perianal disease.bStricturing or penetrating disease cEarly surgery

1. Beaugerie L, et al. Gastroenterology. 2006;130:650-656; 2. Patil S, et al. Gastroenterology. 2012;142:S667; Sands BE, et al. Am J Gastroenterol.

2003;98:2712-2718.

Factor Beaugerie et al1a Patil et al2b Sands et al3c

Younger age at

onset ✓ ✓

Current smoker ✓ ✓

Ileal disease ✓ ✓

Perianal disease ✓

Colonic localization

only ✓

Nausea/vomiting ✓

Abdominal pain ✓

Early exposure to

steroids ✓ ✓ ✓

Looking Beyond Clinical

Remission is Critical

Modigliani R, et al. Gastroenterology. 1990;98:811-817.

Correlation of CDAI vs CDEIS (N=142)

R=0.13; P=NS

Cro

hn

’s D

isease A

cti

vit

y I

nd

ex (

CD

AI)

Crohn’s Disease Endoscopic Index of Severity (CDEIS)

0

0

100

200

300

400

500

600

5 10 15 20 25 30 35

Defining Histologic Remission in Ulcerative

Colitis: Examples of Scoring Systems

Peyrin-Biroulet L, et al. Clin Gastroenterol Hepatol. 2014;12:929-934.

No histologic grading system has been prospectively validated

Study Key Features

Truelove

Three categories

of inflammation

• No significant inflammation; general architecture

of mucosa disturbed

• Mild to moderate inflammation; neutrophils and

eosinophils often present

• Severe inflammation; heavy infiltration by

neutrophils and eosinophils; crypt abscesses and

erosions

Riley et al

Six features assessed on

4-point scale

• Acute inflammatory cell infiltrate

• Crypt abscesses

• Mucin depletion

• Surface epithelial integrity

• Chronic inflammatory cell infiltrate

• Crypt architectural irregularities

Geboes

Six-grade classification system

• Grade 1 (structural and architectural changes)

to Grade 6 (erosion or ulceration)

Impact of Histologic Remission on

Clinical Outcomes

Peyrin-Brioulet L ,et al. Clin Gastroenterol Hepatol. 2014;12:929-934.

Histologic remission and

healing in patients with UC

More likely to be

symptom-free

Reduced risk

of relapse

Reduced risk of

surgery/hospitalization Reduced risk of

colorectal cancer

Long-term clinical, endoscopic,

and histologic remission

More favorable disease course

57.9% of patients with

no significant histologic

inflammation were

symptom-free versus

16.7% of patients with

inflammation

(Isaacs 2010)

Higher relapse rate in patients with presence

versus absence of acute inflammatory cell infiltrate (52% vs. 25%; P=0.02) and

with presence versus absence of crypt

abscesses (78% vs. 27%; P

Mucosal Healing is Associated

with Improved Outcomes

• Achieving mucosal healing (or improvement in

endoscopic activity) is associated with decreased:

– Flares

– Surgery

– Hospitalizations

• Should mucosal healing be the target of treatment?

– Cannot achieve mucosal healing in a significant proportion

– Partial mucosal healing may be good enough

– Limited prospective studies evaluating outcomes in those

treated with mucosal healing as treatment target

Endoscopic Findings and

Subsequent Disease Course

• Definitions of mucosal healing are

not uniform

• Interobserver variability

• Reasonable definition would be total

disappearance of all mucosal ulcers

– Erythema and distorted mucosal vascular

pattern not included

– Is improvement in endoscopic activity just

as important?

Impact of Mucosal Damage on Subsequent

Resection—Ulcerative Colitis

Froslie KF, et al. Gastroenterology. 2007;133:412-422.

Patients with compromised mucosa 1 year after diagnosis

showed a trend toward more surgeries

90

91

92

93

94

95

96

97

98

99

100

Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8

Perc

en

t o

f P

ati

en

ts

MH No MH

MH=Mucosal Healing

Risk of Colectomy According to the Presence

of Severe Endoscopic Lesions—CD

SEL=Severe Endoscopic Lesions (extensive and deep ulcerations on index colonoscopy)

Allez M, et al. Am J Gastroenterol. 2002;97:947-953.

6 8

31 31

43

62

0

20

40

60

80

100

At 1 year At 3 years At 8 years

No SEL

SEL

Pati

en

ts (

%)

Impact of Mucosal Damage on Subsequent

Resection—Ulcerative Colitis

Froslie KF, et al. Gastroenterology. 2007;133:412-422.

Patients with compromised mucosa 1 year after diagnosis showed

a trend toward more surgeries

T i me in Y ears After 1-Y e ar V i sit

P r o

p o

r t i o

n o

f U

C P

a t i

e n

t s

N o

t C

o l e

c t o

m i z

e d

01 2 3 4 5 6 7 8

0

0.92

0.94

0.96

0.98

1.00

Patients with endoscopic activity

at 1-year visit

Patients without endoscopic activity

at 1-year visit

Mucosal Healing After Therapy

Predicts Improved Outcomes

SES=Simple Endoscopic Score

Baert F, et al. Gastroenterology. 2010;138:463-468.

70.8

62.5

27.3

18.2

0

20

40

60

80

100

Remission off steroids Remission off steroids and anti-TNF

SES 0

SES 1-8

Pati

en

ts (

%)

Partial Mucosal Healing May be Enough

to Reduce Risk for Major Endoscopy

Surgery in Crohn’s Disease

MAS=Major Abdominal Surgery

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

0

10

20

30

40

50

60

70

80

90

100

Complete Mucosal Healing Partial Mucosal Healing No Mucosal Healing

Pati

en

ts u

nd

erg

oin

g M

AS

(%

)

14.1 14.0

38.4

Working Definition of Deep Remission

• Fundamentally: State of remission with little or no risk

for disease progression

• Working definition in patients with no bowel damage or

disability

– Resolution of symptoms

– Resolution of ≥1 objective measure of inflammation

(endoscopy, imaging, biomarkers)

• Working definition in patients with existing damage or

disability

– Resolution of ≥1 objective measure of inflammation

– Improvement of symptoms

Colombel JF, et al. Dig Dis. 2012;30 Suppl 3:107-111.

Agenda

• Laboratory markers in IBD: Useful or

unnecessary?

• Deep remission: What does it mean and

how do we achieve it?

• Managing biologics: First- and second-

line treatment options

Case Study

• A 20-year-old male is referred for persistent CD

symptoms

• He had been diagnosed with CD of the ileum and colon

and responded to prednisone therapy

• Upon tapering steroids his abdominal pain and

diarrhea recurred

• He was treated with infliximab monotherapy with a good

result but after 4 months he began to lose response

despite moving to infliximab 10 mg/kg dosing

• He was reassessed and was found to be anemic

What would you do next?

Case Study

• CRP concentrations were assessed:

11 mg/dL

• Trough infliximab levels were absent and

anti-drug antibody levels were high

Would your management of this patient change?

Case Study

• He was switched to adalimumab induction and

maintenance therapy in combination with

azathioprine although his family was concerned

about the risk of lymphoma in young males

• He had an initial response to adalimumab but

developed pancreatitis with azathioprine

• He was treated with methotrexate 12.5 mg weekly

and responded for about 6 months, but developed

increasing symptoms of abdominal pain and

frequent bowel movements

What would you do next?

Case Study

• Adalimumab dosing was increased to 40 mg weekly but

symptoms continued

• Colonoscopy revealed persistent ulcerations across his

transverse colon

• Biopsies demonstrated active inflammation with granulomas

• There was no evidence of cytomegalovirus (CMV) and

Clostridium difficile by polymerase chain reaction (PCR)

was negative

• Trough adalimumab concentrations showed the presence

of adalimumab and no antidrug antibodies

What would you do next?

Clinical Remission in CD: Net Remission

at 6 Months with TNF Antagonists

Adalimumab – CHARM3

28.6 18.3

64.1

47.9

30.7

0

20

40

60

80

100

Open-label induction

week 6

Week 26 remission

Net remission week 26

Pa

tien

ts (

%)

Pbo CzP

21.0 12.3

58.5

39.0

22.8

0

20

40

60

80

100

Pa

tien

ts (

%)

Pbo IFX

17.0 9.9

58.0

40.0

23.2

0

20

40

60

80

100

Pa

tien

ts (

%)

Pbo ADA

Certolizumab pegol – PRECISE 14

18.3 29.5

0

20

40

60

80

100

Pa

tie

nts

(%

)

Pbo CzP

Open-label induction

week 2

Week 30 remission

Net remission week 30

Net Remission Week 26

Open-label induction

week 4

Week 26 remission

Net remission week 26

Infliximab – ACCENT I2 Certolizumab pegol – PRECISE 21

ADA=adalimumab; CZP=certolizumab pegol; IFX=infliximab; Pbo=placebo

1. Schreiber S, et al. N Engl J Med. 2007;357:239-255; 2. Hanauer SB, et al. Lancet. 2002;359:1541-1550;

3. Colombel JF, et al. Gastroenterology. 2007;132:52-62; 4. Sandborn WJ, et al. N Engl J Med. 2007;357:228-237.

Patients failing 5-ASA / Steroids / Immunosuppressives

0%10%20%30%40%50%60%70%80%90%

100%

Infliximab 10mg/kg

Infliximab 5mg/kg

Placebo

Infliximab 8 Weeks

0%10%20%30%40%50%60%70%80%90%

100%

Adalimumab Placebo

Adalimumab 8 Weeks

0%10%20%30%40%50%60%70%80%90%

100%

Golimumab400/200 mg

Golimumab200/100 mg

Placebo

Golimumab 6 Weeks

0%10%20%30%40%50%60%70%80%90%

100%

Infliximab 10mg/kg

Infliximab 5mg/kg

Placebo

Infliximab 54 Weeks

0%10%20%30%40%50%60%70%80%90%

100%

Adalimumab Placebo

Adalimumab 52 Weeks

0%10%20%30%40%50%60%70%80%90%

100%

Golimumab100 mg

Golimumab 50mg

Placebo

Golimumab 54 Weeks

**

** ** *

**

** **

** **

Clinical Remission in UC: ACT (Infliximab), ULTRA-2

(Adalimumab) and PURSUIT (Golimumab)

1

1

2

2

3

4

*P

What is the Role for Combination

Therapy in CD? The SONIC Study P

ati

en

ts (

%)

P

Corticosteroid-free clinical remission at Week 26

Panaccione R, et al. Gastroenterology. 2014;146:392-400.

What is the Role for Combination

Therapy in UC? The UC Success Trial

AZA IFX IFX+AZA

P a t i

e n

t s (

% )

0%

20%

40%

60%

80%

100%

P =0.813

P =0.032

P =0.017

23.68 22.08

39.74

6-MP=6-mercaptopurine; AZA=azathioprine; CI=confidence interval; IFX=infliximab; OR=odds ratio

Toruner M, et al. Gastroenterology. 2008;134:929-936.

Risk Factors for Opportunistic Infections:

The Mayo Experience

• Case-control study

of all opportunistic

infections between

1998-2003

• 2 controls for each

case (matched on

type IBD, age,

gender, residence)

• 100 opportunistic

infections identified

Biologic+AZA is associated with lowest risk

for opportunistic infection

Medication OR (95%CI) P

1 2.7 (1.5-4.8)

Serious Infection and Mortality in Patients

With CD: 5-year Follow-up From TREAT*

• Factors associated with increased mortality risk:

– Prednisone (HR=2.14; P

Safety Considerations with TNF Antagonist

Monotherapy and Combination Therapy

• Infections

• Neoplasia (primarily thiopurines)

• Immunogenicity

• Heart failure

• Demyelination

Humanized

Mouse

Human

Vedolizumab

• Created by grafting

the complementarity-

determining regions of

ACT-1 into a human

IgG1 framework

• Recently approved by

the FDA for CD and

UC

25.5

5.4

24.8

47.1

16.9

40.9

0

20

40

60

80

100

Clinical Response Clinical Remission Mucosal Healing

Pati

en

ts (

%)

Placebo

Vedolizumab

21.6

11.6, 31.7

11.5

4.7, 18.3

16.1

6.4, 25.9 95% CI:

Feagan BG , et al. New Engl J Med. 2013;369:699-710.

P

*P

PBO=placebo; VDZ=vedolizumab

Feagan BG, et al. New Engl J Med. 2013;369:699-710.

10.6

19.1 19.1

26.6

36.0

44.0 45.8

63.5

40.4 46.2 47.9

56.2

0

20

40

60

80

100

Clinical Remission Durable ClinicalResponse

Clinical Remission Durable ClinicalResponse

Pa

tie

nts

(%

)

VDZ/PBO

VDZ/VDZ Q8 Weeks

VDZ/VDZ Q4 Weeks

Column1

25.4 (5.1, 43.8)

29.7 (10.3, 47.7)

24.9 (7.1, 42.6)

27.0 (9.4, 44.6)

26.8 (12.4, 41.2)

29.0 (14.6, 43.3)

38.7 (24.0, 53.4)

29.6 (14.6, 44.6)

Mean % vs VDZ/PBO (95% CI)

VDZ/VDZ Q8W:

VDZ/VDZ Q4W:

Prior Anti-TNF

Antagonist Exposure

(n=149)

Patients Without TNF

Antagonist Exposure

(n=224)

Clinical Remission, Durable Clinical Response at 52

Weeks by Prior TNF Antagonist Exposure in UC

PBO=placebo; VDZ=vedolizumab

Sands BE, et al. Gastroenterology. 2014;147:618-627.

Clinical Remission at Week 6 and 10

in Patients With CD

0

2 0

4 0

6 0

8 0

1 0 0

P = . 4 3 3 P = . 0 4 B 3 1 . 4

1 2 . 0 1 9 . 1

1 2 . 1 1 2 . 1 1 5 . 2

0

2 0

4 0

6 0

8 0

1 0 0

TNF antagonist- failure population

Overall population

TNF antagonist- naive subgroup

P a t i

e n

t s i n

c l i n

i c a l r e

m i s

s i o

n

a t

w e e k 6

, %

TNF antagonist- failure population

Overall population

TNF antagonist- naive subgroup

P a t i

e n

t s i n

c l i n

i c a l r e

m i s

s i o

n

a t

w e e k 1

0 , %

P = . 0 0 1 P < . 0 0 0 1

1 2 . 1

2 6 . 6

1 3 . 0

2 8 . 7

1 6 . 0

3 5 . 3

9 5 % C l ; ( - 4 . 5 , 1 0 . 5 )

n = 1 5 7 n = 1 5 8

( 0 . 1 , 1 3 . 8 ) ( 3 . 3 , 3 5 . 0 ) 9 5 % C l ; ( 5 . 7 , 2 3 . 1 ) ( 7 . 8 , 2 3 . 3 ) ( 2 . 4 , 3 5 . 8 ) ∆ 3 . 1 7. . 0 ∆ 1 9 . 4 ∆ 1 4 . 5 ∆ 1 5 . 7 1 9 . 3

n = 2 0 7 n = 2 0 9 n = 5 0 n = 5 1 n = 1 5 7 n = 1 5 8 n = 2 0 7 n = 2 0 9 n = 5 0 n = 5 1

P B O V D Z

Clinical Remission at W eek 6 Clinical Remission at W eek 10

∆ ∆

GEMINI II: Vedolizumab in Crohn’s Disease

Through Week 52, Maintenance ITT

Sandborn WJ, et al. N Engl J Med. 2013;369:711-721.

21.6

30.1

15.9 14.4

39.0 43.5

31.7

21.4

36.4

45.5

28.8

16.2

0

10

20

30

40

50

60

70

80

90

100

Clinical Remission CDAI-100 Response Glucocorticoid-FreeRemission

Durable ClinicalRemission

Pati

en

ts (

%)

Placebo (N=153) Vedolizumab, every 8 wk (N=154) Vedolizumab, every 4 wk (N=154)

P

Vedolizumab Safety

• ~3000 patients treated in clinical trials, including

~1000 treated for ≥2 years

• Main risk: Nasopharyngitis (13%)

• Infusion reactions are infrequent (4%)

• Abnormal liver function tests seen rarely (

Monitoring Biologics:

Implications of Low Trough

Concentrations

• Disease recurrence

– No longer maintenance but retreatment

• Development of anti-drug antibodies

– Eventual loss of response

Do Not Administer Intermittently!

Monitoring Biologics: What Factors Influence the Pharmacokinetics of TNF

Antagonists?

CRP=C-reactive protein

Ordas I, et al Clin Gastroenterol Hepatol. 2012;10:1079-1087.

Impact on TNF antagonist pharmacokinetics

Presence of anti-drug antibodies

• Decreases drug concentration

Increases clearance

Worse clinical outcomes

Concomitant use of

immunosuppressives

• Reduces anti-drug antibody formation

Increases drug concentration

• Decreases drug clearance

Better clinical outcomes

Low serum albumin concentration • Increases drug clearance

Worse clinical outcome

High baseline CRP concentration • Increase drug clearance

High baseline TNF concentration • May decrease drug concentration by increasing

clearance

High body size • May increase drug clearance

Gender • Males have higher clearance

Confirmed Active Inflammation

Positive ADA

(detectable antibody) Change to another

anti-TNF agent

If persistent disease, change to

treatment with different

MOA (non-anti-TNF agent)

Change to treatment with different MOA

(Non-anti-TNF agent)

Consider adding IS (if monotherapy)

or change to treatment with different MOA

(Non-anti-TNF agent)

Subtherapeutic

concentrations or

undetectable trough

concentration

Therapeutic drug

concentrations

or detectable trough concentration

Increase

dose frequency

ADA=Anti-Drug Antibody; IS=Immunosuppressant; MOA=Mechanism of Action

Afif W, et al. Am J Gastroenterol. 2010;105:1133-1139.

Monitoring Biologics: “Reactive” Testing

The Future: Sphingosine 1-Phosphate

Receptor (S1P1) Agonism?

• Bioactive sphingolipid that is enriched in

the blood and lymph, and functions in

innate and adaptive immunity

• Regulates lymphocyte trafficking, vascular

development and integrity

• S1P1 receptor agonism induces reversible

inhibition of lymphocyte egress from

thymus, lymph nodes and Peyer’s patch

Degagne E, Saba JD. Clin Exp Gastroenterol. 2014.7:205-214.

Sphingosine 1‐Phosphate Receptor 1 (S1P1) Modulation: Mechanism of Action

• S1P1R agonism induces receptor internalization and loss of ability of lymphocytes to respond to S1P gradient

• Lymphocytes become trapped in lymph nodes causing peripheral lymphopenia

• Upon drug withdrawal receptor expression is restored and lymphocytes leave nodes, reversing peripheral lymphopenia

Degagne E, Saba JD. Clin Exp Gastroenterol. 2014;7:205-214.

Conclusions

• Biomarkers are useful surrogates to monitor

disease activity

– Not yet useful as endpoints

• “Deep remission” is a therapeutic goal

– Improved outcomes versus clinical remission

• Biologic therapy is safe and effective for refractory

UC and CD

– Anti-TNF

– Anti-integrin

– Monitoring trough concentrations useful to assess

mechanisms and approach to loss of response