ACR 2011 Medical Passport

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1

ACR 2011 Medical Passport


Highlights of ACR 2011

Chicago, IL

November 2011

Medical Passport Program
-
ACR 2011

2

Faculty

Hector Arbillaga, MD

Philip Baer, MD

Majed Khraishi, MD

Clode Lessard, MD

Robert Offer, MD


Peter Panopalis, MD

Janet Pope, MD

Anthony Russell, MD

Yves Troyanov, MD

Edith Villeneuve, MD

3

Disclosure

Copyright 2011 STA HealthCare Communications
Inc. All rights reserved. This program is published
by STA HealthCare Communications Inc. as a
professional service funded by Bristol
-
Myers Squibb
Canada Co. The information and opinions contained
herein reflect the views and experience of the
authors and not necessarily those of Bristol
-
Myers
Squibb Canada Co., or STA HealthCare
Communications Inc. Any products mentioned
herein should be used in accordance with the
prescribing information contained in their respective
product monograph.

RA Treatment: Existing Disease
-
modifying
Antirheumatic Drugs and Corticosteroids

Hector Arbillaga, MD

Rheumatoid Arthritis Clinical Aspects

Peter Panopalis, MD

Clinical Features of RA; Disease Severity;
Outcomes Research and Metrology

Robert Offer, MD

RA Treatment: Small Molecules, Biologics
and Gene Therapy

Majed Khraishi, MD

Clode Lessard, MD

Edith Villeneuve, MD

Looking Ahead to Kinase Inhibition in
Rheumatoid Arthritis

Anthony Russell, MD

4

Outline

Imaging of Rheumatic Disease

Edith Villeneuve, MD

ACR Plenary Session: Discovery 2011

Robert Offer, MD

ACR Late
-
breaking Abstracts

Janet Pope, MD

Spondylarthropathies: Recent Insights

Majed Khraishi, MD

Impact of Environmental Health

on Autoimmunity

Hector Arbillaga, MD

Osteoporosis and Metabolic Bone Disease:
Clinical Aspects and Pathogenesis

Philip Baer, MD

Orthopedics, Low Back Pain, and
Rehabilitation

Anthony Russell, MD

5

Outline

Systemic Sclerosis (SSc), Fibrosing
Syndromes and Raynaud's
-

Clinical
Aspects and Therapeutics

Clode Lessard, MD

Janet Pope, MD

Complicated Raynaud's Phenomenon

Philip Baer, MD

Vasculitis

Peter Panopalis, MD

New Developments in the Clinical
Evaluation, Immunology and Treatment of
Myositis

Yves Troyanov, MD

Emerging Concepts in the Inflammatory
Myopathies

Yves Troyanov, MD

6

Outline

7

RA Treatment: Existing Disease
-
modifying Antirheumatic Drugs
and Corticosteroids

Highlights of the ACR Concurrent
Abstract Session held Tuesday,
November 8

Summarized by Dr.
Hector Arbillaga

List of Presentations in this Section

Speaker

Title

Abstract #

Villeneuve E

Preliminary Results of a Multicentre
Randomised Controlled Trial of
Etanercept and Methotrexate to Induce
Remission in Patients with Newly
Diagnosed Inflammatory Arthritis

2465

8

Concurrent Abstract Session

RA
Treatment: Existing Disease
-
modifying

Antirheumatic Drugs and Corticosteroids
. ACR 2011
;
Tues., Nov. 8.

MTX + Etanercept or Placebo in RA:

Design of The EMPIRE Study

9

Villeneuve E, et al. Presented at ACR 2011; Presentation #2465.

MTX + Etanercept or Placebo in RA:

Clinical Remission* in the EMPIRE Study

10

*No tender or swollen joints

NB: 5(9.1%) stopped biologics due to sustained remission

Villeneuve E, et al. Presented at ACR 2011; Presentation #2465.

2

24

29

11

16

31

0
5
10
15
20
25
30
35
Week 2
Week 26
Week 52
% of patients

MTX + placebo
MTX + etanercept
p

= 0.051

p

= ns

p

= ns

Does the Presence of ACPA Impact on Efficacy?
DAS28 Remission at Week 52 (EMPIRE Study)

11

Villeneuve E, et al. Presented at ACR 2011; Presentation #2465.

MTX + Etanercept or Placebo in RA:

Conclusions from the EMPIRE Study

12

Villeneuve E, et al. Presented at ACR 2011; Presentation #2465.


Rapid clinical responses were demonstrated
with MTX + ETN combination therapy


At one year, large proportions of both
remission and LDAS were achieved in both
groups


Trend toward earlier clinical responses were
seen in the ACPA
-
positive patients


High response rates to MTX still need to be
explained

13

Rheumatoid Arthritis:


Clinical Aspects

Highlights of ACR Poster and
Concurrent Abstract Sessions,
Sunday November 6

Summarized by Drs. Robert Offer and

Peter Panopalis

List of Presentations in this Section

Speaker / Primary
Author

Title

Abstract #

Bili A

Prolonged


Hydroxychloroquine Use Is Associated
with Decreased Incidence of Cardiovascular
Disease in Rheumatoid Arthritis Patients

1168

Walker CP

Statin Use Is Associated with Decreased Incident
Coronary Artery Events in Rheumatoid Arthritis
Patients

1160

Wolfe F

Reduction in the Risk of Myocardial Infarction in
Bisphosphonate and Calcium/Vitamin D Treated
Rheumatoid Arthritis and Lupus Patients:

A
Longitudinal Cohort Study

2589

Karpouzas GA

Differential Predictors of Mixed and Fully Calcified
Coronary Plaques in Coronary Artery Disease
-
Naïve Patients with Rheumatoid Arthritis

759

14

Poster and Concurrent Abstract Sessions:

Rheumatoid Arthritis: Clinical Aspects. ACR 2011
;
Sun., Nov. 6

List of Presentations in this Section (cont'd)

Speaker / Primary
Author

Title

Abstract #

van Sijl AM

Outward Carotid Arterial Wall Remodelling in
Rheumatoid Arthritis: A Case
-
Control Study

760

Berglin

EH

Comparison of the 1987 ACR and 2010 ACR/EULAR
Classification Criteria for Rheumatoid Arthritis in Clinical
Practice

312

de Hair MJ

The 2010 ACR/EULAR Classification Criteria for
Rheumatoid Arthritis: Earlier Diagnosis At the Expense
of Increased Heterogeneity

313

Kennish

LM

2010 American College of Rheumatology/European
League Against Rheumatism

Rheumatoid Arthritis
Criteria Classifies 67% of Systemic Lupus
Erythematosus and 38% of Psoriatic Arthritis

As
Rheumatoid Arthritis: Implications for Real World Use

314

15

Poster and Concurrent Abstract Sessions:

Rheumatoid Arthritis: Clinical Aspects. ACR 2011
;
Sun., Nov. 6

List of Presentations in this Section (cont'd)

Speaker / Primary
Author

Title

Abstract #

Nicolau

J

Performances of the 2010 ACR/EULAR Classification
Criteria of Rheumatoid Arthritis: Comparison with 1987
ACR Criteria in the Community
-
Based Vera Cohort

315

Ortiz

Garcia AM

Comparison of the 1987 and 2010 Classification
Criteria for Rheumatoid Arthritis in a Population of
Patients with Early Arthritis

319

Bergman MJ

Routine Assessment of Patient Index Data
-
3 (RAPID3),
a Patient
-
Reported Index to Guide a Treat
-
to
-
Target
Strategy for Rheumatoid Arthritis in Usual Care

331

Yokogawa N

To Screen Remission without Formal Joint Count:
Analysis of Routine Assessment of Patient Index Data 3
in Japanese National Database

345

16

Poster and Concurrent Abstract Sessions:

Rheumatoid Arthritis: Clinical Aspects. ACR 2011
;
Sun., Nov. 6

Prolonged Hydroxychloroquine Use in RA

is Associated with Decrease in
CVD

Bili A, et al. Presented at ACR 2011; Poster #1168.

72% reduction

p
<0.001 vs.
never

use

Prolonged Hydroxychloroquine Use in RA

is Associated with Decrease in
CAD

Bili A, et al. Presented at ACR 2011; Poster #1168.

73% reduction

p
<0.001 vs.
never

use

Statin Use is Associated with Decreased
CAD Events in Patients with RA and no CVD


Objective
: To examine the association of statin use with
incident CAD in an inception cohort of RA patients


Method
: Inception cohort of RA patients


1881 patients with newly diagnosed RA, but no pre
-
existing
CVD


Primary outcome: Time to CAD


Secondary outcome: Time to CVD


Key results
: 550 patients were included


In RA patients without CVD, statin use was associated with
a 4% per month decrease in incident CAD


For patients using statins for >17 months, the risk of
incident CAD decreased by 70%

Walker CP, et al. Presented at ACR 2011; Poster #1160.

Bisphosphonates and CAD

Treatment

Odds

ratio for
MI (95% CI)

Bisphosphonate

alone

0.75 (0.58
-
0.98)

Calcium +
vitamin

D

0.57 (0.42
-
0.77)

Bisphosphonate

+ calcium +
vitamin D

0.38 (0.22
-
0.66)


Recent studies have
reported increased
survival on
bisphosphonates and
increased CAD in
patients using
”excessive” calcium
supplements


This study adds
support to a protective
effect of
bisphosphonates by
reducing MIs


Wolfe F, et al. Presented at ACR 2011; Presentation #2589.

Calcified Coronary Artery Plaques in RA: Distribution
of Plaque Types Compared with Controls

70

14

16

51

28

21

0
10
20
30
40
50
60
70
80
Non-calcified
Mixed
Full calcified
% of affected segments

Controls
RA
Karpouzas GA, et al. Presented at ACR 2011; Presentation #759.

p

= 0.004

p

= 0.0002

Calcified Coronary Artery Plaques in RA:
Key Findings


Predictors of higher mixed plaque prevalence:


DAS28
-
3 ≥ 3.2


High CRP


Treatment with a TNF
-
α

inhibitor was
associated with a 70% lower risk for mixed
plaque presence


Even in the absence of good clinical response

Karpouzas GA, et al. Presented at ACR 2011; Presentation #759.

Outward Carotid Arterial Wall

Remodelling in RA: A Case
-
Control Study


Objective
: To assess arterial remodelling in RA


Method
: B
-
mode carotid ultrasonography was
performed in 96 RA and 274 healthy controls


Investigators assessed various parameters
such as
intima
-
media thickness (IMT), inter
-
adventitial diameter (IAD) and lumen diameter
(LD)


Results
: RA is associated with outward
remodelling


Interpretation
: This is relevant in view of the
association between outward remodelling and
plaque instability and rupture


van Sijl AM, et al. Presented at ACR 2011; Presentation #760.

Comparisons of the 1987 ACR and 2010 ACR/EULAR
Classification Criteria in Early Arthritis


The 2010 ACR/EULAR criteria had higher
sensitivity but lower specificity than 1987 ACR
criteria in a cohort of early arthritis patients
1,3


Use of the 2010 ACR/EULAR criteria clearly
allows earlier diagnosis of RA, although some
patients with self
-
limiting disease may be
falsely diagnosed with RA
2


Patients fulfilling 2010 ACR/EULAR criteria
during early disease are less likely to be
autoantibody positive and more likely to have
mono
-
arthritis than those fulfilling 1987 ACR
criteria
2


1. Berglin EH, et al. Presented at ACR 2011; Presentation #312.

2. de Hair MJ, et al. Presented at ACR 2011; Presentation #313.

3. Kennish LM, et al. Presented at ACR 2011; Presentation #314.

Comparisons of the 1987 ACR and 2010 ACR/EULAR
Classification Criteria in Early Arthritis


2010 criteria have low specificity and will incorrectly
label those as having RA when in fact they have another
form of inflammatory arthritis
1


Physicians need to be aware of this when applying the
new criteria


Using a very early community
-
based cohort, the 2010
ACR/EULAR criteria classified slightly more patients
than the 1987 ACR criteria but otherwise they performed
similarly
2


In another EA population, there were no relevant
differences in RA disease identification when the 1987
or the 2010 classification criteria are implemented,
except for a higher specificity for the 1987 set
3


25

1. Kennish LM, et al. Presented at ACR 2011; Presentation #314.

2. Nicolau J, et al. Presented at ACR 2011; Presentation #315.

3. Ortiz Garcia AM, et al. Presented at ACR 2011; Presentation #319.

The Use of RAPID3 for a

Treat
-
to
-
Target Strategy


Background
: RAPID3 is a composite measure
of disease activity, requiring only 3 patient self
-
reported measures: Physical function, pain and
patient estimate of global disease status


Method
: The authors compared RAPID3 to
DAS28 and to CDAI in a treat
-
to
-
target approach
in a usual care setting


Findings
: RAPID3 appears similar to DAS28 and
CDAI for recognition of low activity/severity or
remission versus high activity/severity to guide
a treat
-
to
-
target strategy for RA


Bergman MJ, et al. Presented at ACR 2011; Presentation #331.

Use of the RAPID3 to Assess Remission

N
••=4479

Sensitivity

(%)

Specificity

(%)

SDAI remission

91

93

CDAI remission

89.3

93.8

DAS28 remission

76.9

84.7

RAPID3 < 2

90.5

79.4

RAPID3 < 3

95.4

31.6

Yokogawa N, et al. Presented at ACR 2011; Presentation #345.

28

Clinical Features of Rheumatoid
Arthritis; Disease Severity;
Outcomes Research and
Metrology

Highlights of an ACR Poster
Session, Tuesday, November 8

Summarized by Dr.
Robert Offer

List of Presentations in this Section

Speaker

Title

Abstract #

Knevel R

Genetic Predisposition of the Severity
of Joint Destruction in Rheumatoid
Arthritis; A Population Based Study.

2136

Clowse ME

Contraception Use in Women with
Rheumatoid Arthritis

2109

29

Poster Session: Clinical Features of Rheumatoid Arthritis; Disease Severity;

Outcomes Research and Metrology. ACR 2011
;
Tues., Nov. 8.

Susceptibility

to RA is Partly Inherited.

What About
Severity

of RA?


Objective
: To

evaluate whether the severity of
joint destruction in RA is heritable


Method
: Data analysis of records from 325
patients in an Icelandic database with complete
radiographs of hand and feet and relevant
genealogic information


Results
: Significant associations between
degree of relatedness and similarity in joint
destruction rates were observed


Knevel R, et al. Presented at ACR 2011; Poster #2136.

Are Women on RA Medications Using
Contraception Appropriately?

Contraceptive method

Failure rate*

Use in this

cohort


Ineffective

36

(34%)

No method

85%

16

Abstinence

11

Withdrawal

27%

4

Rhythm

method

25%

3

Condoms

15%

9

Effective

24 (22.6%)

Estrogen
-
combination

pills

8%

17

Progestin
-
only pills

5%

2

Depo
-
Provera
®

injection

3%

1

Intra
-
uterine device

0.2%

4

Sterilization

46 (43.4%)

*% of women who conceive using this method over a year


Some women use multiple forms of contraception

Clowse ME, et al. Presented at ACR 2011; Poster #2109.

FDA Pregnancy Categories: RA Medications

Clowse ME, et al. Presented at ACR 2011; Poster #2109.

FDA

Category

Definition

DMARDs and Biologics

A

Extensive human safety data

demonstrating
no fetal risk

B

Reassuring

animal data with little/no human
data to confirm this; OR animal studies show
risk but human data showing no risk

TNF

inhibitors

Sulfasalazine (D at term)

C

Either no animal studies or animal studies
suggest no risk,

no human data to confirm
this

Hydroxychloroquine

Abatacept

Rituximab

D

Some evidence of adverse reactions in fetus,

but potential benefit may outweigh the risks

X

Documented fetal

harm and the benefit of
drug does not outweigh the risk

Methotrexate

Leflunomide

Women
taking
medication

Contraception

Ineffective

Effective

Sterilization

Class
B

TNFi

56 (53%)

23 (41%)

14

(25%)

19 (34%)

SSZ

6 (6%)

1 (17%)

2 (33%)

3 (50%)

Clas
s
C

HCQ

20 (19%)

6 (30%)

7 (35%)

7 (35%)

ABA or
RTX

13 (12%)

3 (23%)

0

10 (77%)

Class
X

MTX or
LEF

59 (56%)

17 (28%)

14 (23%)

28 (48%)

Contraceptive Use by RA Medication

Clowse ME, et al. Presented at ACR 2011; Poster #2109.

Are women on RA medications using
contraception appropriately? Conclusions


Almost half of women with RA in this cohort took
FDA class X medications


28% of these women were using ineffective
contraception, leaving them at high risk for
pregnancy


5
-
fold more women using ineffective contraception
had a prior elective termination than either women
using effective contraception or sterilization


This study highlights the importance of
contraceptive education and prescription by
rheumatologists to ensure that patients taking
potentially teratogenic medications do not become
pregnant

Clowse ME, et al. Presented at ACR 2011; Poster #2109.

35

RA Treatment: Small Molecules,
Biologics and Gene Therapy

Highlights of ACR Poster
Sessions, November 6
-
8

Summarized by Drs.
Majed Khraishi,

Clode Lessard, Robert Offer, Janet Pope and


Edith Villeneuve

List of Presentations in this Section

Speaker /
primary author

Title

Abstract #

Pope

J

The Effectiveness of Abatacept in a Large
Rheumatoid Arthritis Real World Practice:


Changes
in the HAQ Over Time and Durability of Response

1222

Yazici Y

Comparative Effectiveness and Time to Response
Among Abatacept, Adalimumab, Etanercept and
Infliximab for the Treatment of Rheumatoid Arthritis
in a Real World Routine Care Registry

2233

Fleischmann R

Treatment Outcomes Based on Methotrexate Dose
Range in Patients with Rheumatoid Arthritis
Receiving Etanercept Plus Methotrexate Versus
Methotrexate Alone

441

36

Poster Sessions

RA Treatment: Small Molecules, Biologics

and Gene Therapy. ACR 2011
;
Nov. 6
-
8.

List of Presentations in this Section (cont'd)

Speaker /
primary author

Title

Abstract #

Emery P

Evaluation of the Association Between Disease
Activity and Risk of Serious Infections in Subjects
with Rheumatoid Arthritis When Treated with
Etanercept or DMARDs

429

Yonemoto Y

Direct Comparison of Four Biologics in Biologic
-
naïve Rheumatoid Arthritis Patients

1236

Strangfeld A

Impact of Different Biologic Agents on the
Improvement of Fatigue

461

Meissner B

Real
-
World Switching Patterns in RA Patients
Receiving Abatacept, Adalimumab, Etanercept or
Infliximab As Second
-
Line Biologic Therapy

2198

37

Poster Sessions

RA Treatment: Small Molecules, Biologics

and Gene Therapy. ACR 2011
;
Nov. 6
-
8.

List of Presentations in this Section (cont'd)

Speaker

Title

Abstract #

Burmester JR

Tofacitinib (CP
-
690,550), An Oral Janus Kinase
Inhibitor, in Combination with Methotrexate, in
Patients with Active Rheumatoid Arthritis with An
Inadequate Response to

Tumor Necrosis Factor
-
Inhibitors: A 6
-
Month Phase 3 Study

718

Yamanaka H

Tofacitinib (CP
-
690,550), An Oral Janus Kinase
Inhibitor, As Monotherapy or with Background
Methotrexate in Japanese Patients with Rheumatoid
Arthritis: A Phase 2/3 Long
-
Term Extension Study

1215

Vanhoutte F

GLPG0634 Shows Selective Inhibition of JAK1 and
Maintained

JAK
-
STAT Suppression in Healthy
Volunteers

2210

38

Poster Sessions

RA Treatment: Small Molecules, Biologics

and Gene Therapy. ACR 2011
;
Nov. 6
-
8.

List of Presentations in this Section (cont'd)

Speaker

Title

Abstract #

Urata Y

Treating to Target Matrix Metalloproteinase 3
Normalisation Together with Disease Activity Score
Below 2.6 Yields Better Effects Than Each Alone In
Rheumatoid Arthritis Patients: Treating to Twin
Targets; T
-
4 Study

1207

Matsubara T

SNP Algorithms for Prediction of Efficacy and
Adverse Events of Abatacept

1263

39

Poster Sessions

RA Treatment: Small Molecules, Biologics

and Gene Therapy. ACR 2011
;
Nov. 6
-
8.

The Effectiveness of Abatacept in a Large
RA Real
-
World Practice


Background
:


Long
-
term, real
-
world effectiveness data in
RA patients using abatacept in a large multi
-
centre cohort are lacking


There is a high drop out rate with some
biologics, such as TNF inhibitors, within the
first two years of treatment


NNT for improving HAQ in RA for TNFi is 1.94

Pope J, et al. Presented at ACR 2011; Poster #1222.

The Effectiveness of Abatacept in a Large
RA Real
-
World Practice


Objective
: T
o determine the real
-
world
effectiveness of abatacept in RA patients


Assessments
:


Changes in health assessment questionnaire
(HAQ)


Proportion of patients continuing abatacept
over time


NNT to improve HAQ by at least the minimally
clinical important difference (MCID) of 0.22.


Comparison of TNFi
-
exposed
vs.

non
-
exposed patients


Pope J, et al. Presented at ACR 2011; Poster #1222.

Abatacept in Real
-
World Practice:

Baseline Characteristics and Disposition

Parameter

Post DMARD

N=369

Post TNFi

N=1,402

Total Cohort

N=1,771

p

Value

Mean
age,

years (SD)


58.80 (13.65)

57.28 (13.10)

57.60 (13.23)

0.0496

Mean
time since
diagnosis, years (SD)


13.25 (10.83)

17.36 (10.92)

16.53 (11.02)

<0.001

Female
gender,
n (%)


260 (70.46)

1,107 (78.96)

1,367 (77.19)

<0.001

Disease
Severity,

n (%)


Mild


1 (0.27)

4 (0.29)

5 (0.28)

0.736

Moderate


22 (5.96)

104 (7.42)

126 (7.11)

Severe


346 (93.77)

1,291 (92.08)

1,637 (92.43)

NA


0 (0.00)

3 (0.21)

3 (0.17)

Mean durability of
treatment,

months (SD)

26.12 (0.86)

25.75 (0.58)

26.79 (0.53)

< 0.001

Pope J, et al. Presented at ACR 2011; Poster #1222.

Abatacept in Real
-
World Practice:

Change in HAQ Scores

0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
Baseline
12 months
24 months
36 months
Mean HAQ Score

Post DMARD
Post TNFi
Total cohort
Pope J, et al. Presented at ACR 2011; Poster #1222.

Abatacept in Real
-
World Practice:

Overall Treatment Durability

Pope J, et al. Presented at ACR 2011; Poster #1222.

Abatacept in Real
-
World Practice:

Treatment Durability by Prior Treatment

Pope J, et al. Presented at ACR 2011; Poster #1222.

Abatacept in Real
-
World Practice:

Achievement of Clinically Important HAQ Change

Pope J, et al. Presented at ACR 2011; Poster #1222.

MCID

# of prior

biologics

OR

95%
CI

p

value

NNT
(1/ARR)

Modified
NNT

0
biologics

Modified
NNT ≥ 1
biologic

0

≥1

Yes, n
(%)

213
(70.1)

806
(71.4)

0.94

0.71
to
1.24

0.65

75.5

1.43

1.40

No, n
(%)

91

(29.9)

323
(28.6)

Abatacept in Real
-
World Practice:

Conclusions


A
batacept is effective in improving function in RA, as
measured by HAQ, despite long disease duration and in
1st biologic and post exposure to other biologics


HAQ continued to improve over the first 2 years in both
1st and post
-
other biologics


The real world durability of abatacept is better as first
biologic


The overall drug survival in this large study seems
similar to other biologics despite 79% having previous
TNFi exposure


NNT to improve HAQ by at least MCID was 1.4 to 1.43
and not different between those pre
-

or post
-

other
biologics and is a very good NNT



Pope J, et al. Presented at ACR 2011; Poster #1222.

48

Comparative effectiveness and time to
response among adalimumab, abatacept,
etanercept and infliximab for the
treatment of RA in a real world routine
care registry

Yusuf Yazici, MD, Maria F Filopoulos, MD,

Christopher J Swearingen, PhD


NYU Hospital for Joint Diseases, New York, USA,

University of Arkansas for Medical Sciences, Little Rock, AR


Yazici
et al
. ACR 2011

49

Method

Prospective analysis from NYU Arthritis Registry
Monitoring Database (ARMD) since 2005 in all patients
seen in routine care.



Each patient in this setting completes 1
-
page MDHAQ at every visit


Usage of the biologic medications abatacept, adalimumab,
etanercept and infliximab along with self
-
reported disease activity
and clinic measures were abstracted.


Treatments were considered to be independent of each other as no
individual received biologic medications in combination.

Adapted from Yazici
et al
. ACR 2011

50

Method

Time to first response defined as


Improvement in RAPID3 of at least 3.6 (clinically important
difference).

Change
from biologic medication initiation to first response for self
-
reported disease activity and clinic measures was estimated.

For those individuals with no response, time to last follow
-
up was
calculated.

Differences in time to first response between biologic medications
were estimated using Cox proportional hazards model.

Adapted from Yazici
et al
. ACR 2011

51

RAPID3 component scores at baseline

Adapted from Yazici
et al
. ACR 2011

52

Cumulative incidence of time to RAPID3 >3.6
response adjusted for age and disease duration

Cumulative incidence of time to RAPID3 >3.6 response adjusted for age and disease duration

Cumulative incidence of time to RAPID3 >3.6 response adjusted for age and disease duration

Adapted from Yazici
et al
. ACR 2011

53

Conclusion

O
verall efficacy of abatacept, adalimumab, etanercept
and infliximab was similar
.


In addition, no differences in time to response was
shown among these biologic agents when treating
RA patients.


With no difference in clinical outcomes or response
time, most treatment decisions may be based on
ease of use, safety data and long term survival of
respective biologics agents when they are being
considered for RA treatment.


What is the Optimal Dose of MTX

When Used in Combination with Etanercept?

MTX Dose

Range (mg)

Low


(≤12.5)

Medium

(12.6


17.5)

High

(≥ 17.6)

n

49

60

111

Median MTX dose

7.5

15

20

DAS28 < 2.6, %

46.9

58.3

55.0

DAS44 < 1.6, %

49.0

55.0

55.0

ACR70, %

41.7

57.6

52.3

HAQ ≤ 0.5, %

SSKT

R9KP

RQK9

dood 䕕iAo
牥獰on獥I B

TPKR

8PKP

T2KN

T卓p
Δ

≤ 0.5, %

80.9

90.0

73.9

Fleischmann R. Presented at ACR 2011; Poster #441.

Does RA Disease Activity Influence Risk of
Serious Infection (BSRBR)?


No increase of infection rates with DMARDs and
Etanercept when adjusted for other factors


Significant increase of infection rate with higher
DAS at baseline

Emery P, et al. Presented at ACR 2011; Poster #429.

HR for serious
infection

95% CI

Etanercept vs.
DMARD

1.066

0.86 to 1.32

DAS (per integer
increase)

1.156

1.06 to 1.26

Direct Comparison of 4 Biologics

in Biologic
-
Naïve RA Patients


144 biologic
-
naïve patients starting a biologic
from July 2008 onward

Yonemoto Y, et al. Presented at ACR 2011; Poster #1236.

Baseline Characteristic

IFX (n=37)

ETN (n=39)

TCZ (n=27)

ADA (n=39)

p

Male, %

16

21

22

28

0.65

Age, years

59

59

63

60

0.33

RA
duration, months

105

131

149

132

0.28

Concomitant MTX, %

100

54

41

87

<0.01

MTX dosage, mg/wk

6.6

6.3

5.3

6.2

<0.01

Concomitant PSL, %

84

67

74

59

0.11

PSL dosage, mg/day

4.5

4.8

4.8

5.0

0.77

CRP (mg/dL)

2.66

2.81

4.27

2.62

<0.01

ESR (mm/hr)

53

54

71

52

0.41

MMP
-
3

(ng/dL)

275.2

241.0

315.4

286.0

0.74

DAS
-
28 (ESR)

4.9

4.8

5.5

4.8

0.73

DAS
-
28 (CRP)

3.9

3.8

4.6

3.9

<0.05

Direct Comparison of 4 Biologics

in Biologic
-
Naïve RA Patients: Results


At 6 months:


All agents improved DAS28
-
ESR significantly


Significantly greater change in DAS28 for TCZ
vs
. INF and ADA


No ∆ in drug survival rate


TCZ 100%


ETN 92 %


ADA and INF 89%

Yonemoto Y, et al. Presented at ACR 2011; Poster #1236.

Direct Comparison of 4 Biologics

in Biologic
-
Naïve RA Patients: Interpretation


All therapies achieve similar results
1


Slightly better response of TCZ group possibly due
to suppression of APR
1


Will this be generalizable and sustained?


Safety and tolerability differences may emerge over
the long term


At ACR 2011, several long
-
term studies presented


9 years of etanercept monotherapy
2


8 years of adalimumab
±

MTX
3


2 years of abatacept in a real
-
world setting
4

1. Yonemoto Y, et al. Presented at ACR 2011; Poster #1236.

2. Fleischmann RM, et al. Presented at ACR 2011; Poster #1217.

3. Breedveld FC, et al. Presented at ACR 2011; Poster #1231.

4. Pope J, et al. Presented at ACR 2011; Poster #1222.
\

Fatigue: Are All Biologics Equal?

Treatment

No. of
patients

No fatigue at 6
months

Significant
improvement

Adj. OR

95% CI

Adj.

OR

95% CI

DMARD

1,059

Ref.

-

Ref.

-

Etanercept

1,272

1.7*

1.3 to 2.1

2.0*

1.7

to 2.5

Infliximab

507

1.6*

1.2

to 2.2

1.7*

1.3 to 2.2

Adalimumab

1,407

1.4*

1.1 to 1.7

1.8*

1.4 to 2.2

Rituximab

783

1.3

0.9 to 1.8

1.6*

1.2 to 2.1

Abatacept

180

1.1

0.7 to 1.9

1.4

0.9 to 2.1

Tocilizumab

222

1.6*

1.0 to 2.4

2.0*

1.4 to 2.9

*Statistically significant difference vs. DMARD group

Strangfeld A, et al. Presented at ACR 2011; Poster #461.

Fatigue: Are All Biologics Equal?

Strangfeld A, et al. Presented at ACR 2011; Poster #461.

7

6

5

4

Baseline

3 months

6 months

DMARD

Etanercept

Infliximab

Adalimumab

Rituximab

Abatacept

Tocilizumab

Mean level of fatigue

Real
-
life Biologic Switching Patterns


Among patients on a
2
nd

biologic for RA:


78.5% had switched from one anti
-
TNF agent to
another


2.6% had switched from abatacept to anti
-
TNF


20.0% had switched from anti
-
TNF to abatacept


21.9% of the above patient switched to a
3
rd

biologic
within 1 year


23.3% of 2
nd
-
line anti
-
TNF patients switched to a
3
rd

agent


15.9% of 2
nd
-
line abatacept patients switched to a
3
rd

agent

61

Analysis of pharmacy data in the US

Meissner B, et al. Presented at ACR 2011; Poster #2198.

Tofacitinib in TNF Failures:

The ORAL Step Study


At Month 3, all placebo patients blindly
advanced to tofacitinib 5 or 10 mg BID


Primary assessments: ACR20, HAQ
-
DI,
DAS28(ESR) <2.6, safety and tolerability

Burmester JR, et al. Presented at ACR 2011; Presentation #718.

Tofacitinib in TNF Failures

(ORAL Step Study) : Prior DMARD Use

n (%)

PBO


5

n=66

PBO


10

n=66

5

mg

n=133

10

mg BID
n=134

Prior TNFi

66 (100)

66 (100)

132 (99.2)*

132

(98.5)


Adalimumab

Certolizumab

Etanercept

Golimumab

Infliximab

36

(54.5)

7 (10.6)

29 (43.9)

2 (3.0)

27

(40.9)

42 (63,6)

4 (6.0)

28

(42.4)

5 (7.6)

16 (24.2)

65 (48.9)

9 (6.8)

65 (48.9)

5 (3.8)

56 (42.1)

74 (55.2)

9

(6.7)

57 (42.5)

8 (6.0)

42 (31.3)

Other biologics

4 (6.1)

10 (15.2)

21 (15.8)

11

(8.2)

Non
-
biologic
DMARDs other

than MTX

16 (24.2)

17 (25.8)

53 (39.8)

37 (27.6)

*One patient had been previously treated with a biosimilar version of etanercept;


Two patients had no previous treatment with TNFi (MTX, n=1; MTX + sulfasalazine, n=1)

Burmester JR, et al. Presented at ACR 2011; Presentation #718.

Tofacitinib in TNF Failures: ACR20
Responses at Month 3

24.4

41.7*

48.1


0
10
20
30
40
50
60
Placebo
Tofacitinib 5 mg
Tofacitinib 10 mg
% of patients

*
p
≤0.05;

p
<0.0001

Burmester JR, et al. Presented at ACR 2011; Presentation #718.

Tofacitinib in TNF Failures: ACR20 Responses
at Month 3 by Previous TNFi Exposure

30.6

10.8

22.2

43.4*

37.8*

36.4

48.3

53.3


41.7

0
10
20
30
40
50
60
1 Prior TNFi
2 Prior TNFis
3 Prior TNFis
% of patients

Placebo
Tofacitinib 5 mg
Tofacitinib 10 mg
*
p
≤0.05;

p
<0.0001

Burmester JR, et al. Presented at ACR 2011; Presentation #718.

Tofacitinib in TNF Failures: Laboratory Tests

Month 3

Month 6

PBO

5 mg
BID

10

mg
BID

PBO


5

PBO


10

5 mg
BID

10 mg
BID

LS mean

change from baseline

Neutrophil count, 10
3
/mm
3

0.13

-
0.93


-
0.81


-
0.77*

-
0.69*

-
0.73


-
0.77


Hemoglobin, g/dL

-
0.10

0.11

0.01

0.11

0.03

0.16

-
0.02

Δ LDL
-
C f牯m baselineI

B

-
MKP

NNKN


11.7


9.6


16.2


11.8


10.4


Δ HDL
-
C from baseline,

%

0.03

13.4


15.3


14.2


17.3


16.4


18.0


Serum creatinine (mg/dL)

0.05

0.04

0.05

0.04

0.06

0.05

0.06*

Confirmed incidence, n (%)

Neutropenia

(500
-
1499 cells/mm
3
)

0

1 (<1)

0

0

0

0

1 (<1)

Decreased hemoglobin

(
-
1 to
-
3 g/dL)

12
(10.2)

9
(7.8)

16
(12.9)

4
(8.0)

5
(10.4)

5
(5.0)

15

(14.7)

*
p
≤0.05;

p
<0.0
\
01;

p
<0.0001

Burmester JR, et al. Presented at ACR 2011; Presentation #718.

Tofacitinib in TNF Failures

(ORAL Step Study: Conclusions


Tofacitinib 5 and 10 mg BID demonstrated statistically
significant and clinically meaningful:


Reductions in the signs and symptoms of RA


Improvements in physical function


Achievement of DAS
-
defined remission


Evidence for rapid onset of efficacy was also demonstrated
with an increase in efficacy response through 6 months of
treatment


Changes in mean neutrophil counts, hemoglobin, cholesterol
(HDL and LDL) were observed over the first 3
-
month treatment
period; mean changes stabilized thereafter. ALT >3x ULN was
uncommonly reported; AST >3x ULN not reported


One death was reported; no opportunistic infections or cases
of TB were observed


No new safety signals were detected


Burmester JR, et al. Presented at ACR 2011; Presentation #718.

Long
-
term Tofacitinib Use in Japanese
Patients with RA: ACR20 Results

68

Yamanaka H, et al. Presented at ACR 2011; Poster #1215.

Early Research with GLPG0634,

A Novel, Selective JAK1 Inhibitor


Key findings
:


GLPG0634 potently inhibits JAK1 with a 30
-
fold
selectivity over JAK2 in whole blood assays


In healthy volunteers, GLPG0634 is well tolerated
in the pharmacologic active dose range


PK/PD relationship is consistent with once
-
daily
dosing


No signs indicative of anemia were observed after
10
-
days of dosing


Results support progression into efficacy
evaluation in RA patients


69

Vanhoutte F, et al. Presented at ACR 2011; Poster #2210.

Research Presented at ACR 2011 With
Possible Implications for Future Practice


Treating to target MMP
-
3 together with DAS28 <
2.6 yields better results than each target alone
in RA (Treating to Twin Targets [T
-
4] Study)
1



SNP algorithms predict efficacy and adverse
events of abatacept
2


Remission: sensitivity
-
specificity 91
-
97%


AEs: sensitivity
-
specificity 95
-
100%

1. Urata Y, et al. Presented at ACR 2011; Poster #1207.

2. Matsubara T, et al. Presented at ACR 2011; Poster #1263.

71

Looking Ahead to Kinase
Inhibition in Rheumatoid
Arthritis

Highlights of an ACR Clinical
Symposium, Sunday, November 6

Summarized by Drs. Robert Offer and
Anthony Russell

List of Presentations in this Section

Speaker

Title

Genovese

MC

Which Kinase Pathways are Important in
Rheumatoid Arthritis and How Do We Decide
What to Target?

Weinblatt ME

What Does the Data Inform Us About Safety and
Efficacy of Kinase Inhibitors?

Fleischmann RM

Where Will These Agents Fit into Our Treatment
Paradigm?

72

Clinical Symposium: Looking Ahead to Kinase Inhibition in Rheumatoid Arthritis

ACR 2011; Sun., Nov. 6 25.

Simple Description of JAK Pathway

Tyrosine kinases phosphorylate

Receptors are activated by binding with the ligand

JAKs bind and activate STATs

STATs migrate into the nucleus and cause
deregulation or gene transcription

73

Genovese MC. Clinical Symposium " Looking Ahead to Kinase Inhibition in
Rheumatoid Arthritis". Presented at ACR 2011.

JAK Signalling

JAK
1

JAK2

JAK3

TYK2

Type I and Type II

cytokine receptors

Type II cytokine

receptors

Common
γ

chain
elicits signals from IL
-
2
receptor family,

IL
-
4 receptor family

Type 1 interferons
α
/
β

Common
γ

chain

elicits signals from IL
-
2

receptor family,

IL
-
4 receptor family

Receptors for

hormones

Erythropoietin

Thrombopoietin

Prolactin

Growth hormone

IL
-
2,4,7,9,15,21

IL
-
12 receptor

B1 subunit (IL
-
12/23)

IL
-
2, 4, 7, 9,15, 21

GM
-
CSF receptor
family (IL
-
3 R, IL
-
5R
GM
-
CSFR)

gp130 receptor family

IL
-
6, 11, 27, 31

gp130 receptor family

IL
-
6, 11, 27, 31

Type 1 interferons

α
L
β

Type 1 interferons

α
L
β

Type II interferons
γ

Type II interferons
γ

74

Genovese MC. Clinical Symposium " Looking Ahead to Kinase Inhibition in
Rheumatoid Arthritis". Presented at ACR 2011.

Other Enzymes: SYK and BTK

Enzyme

Pathway

Spleen tyrosine kinase

(
SYK)

FcγR and B
-
捥ll 牥捥pto爠獩gnalling

Bruton’s Tyrosine Kinase (BTK)

A捴ivated b礠卙p

75

Genovese MC. Clinical Symposium " Looking Ahead to Kinase Inhibition in
Rheumatoid Arthritis". Presented at ACR 2011.

Tofacitinib (JAK Inhibitor): 6
-
week Phase II
Study in RA in
Monotherapy

76

Kremer JM, et al. Arthritis Rheum 2009; 60(7):1895
-
905.

Cited by Weinblatt ME. Clinical Symposium " Looking Ahead to Kinase Inhibition in
Rheumatoid Arthritis". Presented at ACR 2011.

Tofacitinib (JAK Inhibitor): Phase II Study in RA
in
Combination with MTX



Week 12 Results

77

Kremer JM, et al. Presented at ACR 2008; abstract L13.

Cited by Weinblatt ME. Clinical Symposium " Looking Ahead to Kinase Inhibition in
Rheumatoid Arthritis". Presented at ACR 2011.

37.7

60.6

58.7

60.0

0
10
20
30
40
50
60
70
Placebo + MTX
5 mg + MTX
15 mg + MTX
20 mg + MTX
% of patients with ACR responses

ACR20
ACR50
ACR70
Tofacitinib (JAK Inhibitor): Phase II Study
in RA in
Monotherapy



Week 12 Results

78

Kanik K, et al.
Ann Rheum Dis 2009; 68(Suppl3):123.

Cited by Weinblatt ME. Clinical Symposium " Looking Ahead to Kinase Inhibition in
Rheumatoid Arthritis". Presented at ACR 2011.

28.8

63.3

75.4

75.4

47.2

0
10
20
30
40
50
60
70
80
Placebo
Tofacitinib 5
mg
Tofacitinib 10
mg
Tofacitinib 15
mg
Adalimumab
40 mg eow
% of patients with ACR responses

ACR20
ACR50
ACR70
Tofacitinib (JAK Inhibitor): Phase III Study
in RA in
Monotherapy



Week 12 Results

79

*
p
< 0.0001

Fleischmann RM, et al. Presented at ACR 2010; abstract L8.

Cited by Weinblatt ME. Clinical Symposium " Looking Ahead to Kinase Inhibition in
Rheumatoid Arthritis". Presented at ACR 2011.

ACR20

Δ

HAQ

DAS Remission

Placebo

27%

-
0.2

4%

5 mg bid

60%*

-
0.5*

6%

10 mg bid

66%*

-
0.6*

9.6%

Tofacitinib (JAK Inhibitor): Phase III Study in RA in
Combination with DMARDs



Week 24 Results

80

*
p
< 0.0001

Kremer J, et al.
Ann Rheum Dis 2011; 70(Suppl3):170.

Cited by Weinblatt ME. Clinical Symposium " Looking Ahead to Kinase Inhibition in
Rheumatoid Arthritis". Presented at ACR 2011.

ACR20

Δ

HAQ

DAS Remission

Placebo

31%

-
0.21

3%

5 mg bid

53%*

-
0.46*

11%

10 mg bid

58%*

-
0.56*

15%*

Tofacitinib (JAK Inhibitor) Combined

with Atorvastatin


Background
: Total cholesterol and LDL increased up to 25% in
tofacitinib studies. No drug interactions between tofacitinib
and atorvastatin


Objective
: Evaluate safety and LDL with atorvastatin plus tofa


Design
: 6 wk open run in of Tofa 10 mg bid and then 6 wk DB
of tofa plus atorvastatin 10 mg vs tofa plus placebo


Endpoint
: % change in LDL from wk 6 (start of DB) to wk 12


Results
:


35% reduction of LDL in the atorvastatin group to mean of
80 mg/dL (~2.0 mmol/L)


Total cholesterol, Apo B and triglycerides also decreased


No safety signal with the combination


81

McInnes I, et al.
Ann Rheum Dis 2011; 70(Suppl3):169.

Cited by Weinblatt ME. Clinical Symposium " Looking Ahead to Kinase Inhibition in
Rheumatoid Arthritis". Presented at ACR 2011.

Tofacitinib Phase 3

Monotherapy Study in RA


Objective
: To compare the efficacy and safety of
tofacitinib to adalimumab and to placebo in active
RA


Subjects
: 717 patients with active RA and
inadequate response to methotrexate


Methodology
: Subjects were randomized (4:4:4:1:1
ratio) to


Tofacitinib 5 mg BID SC Q2W);


Tofacitinib 10 mg BID SC Q2W;


Adalimumab 40 mg SC Q2W;


Placebo


tofacit楮ib 5g BI䐠S䌠C2W;r


Placebo


tofacit楮ib 10g⁂I䐠S䌠Q2W


82

van Vollenhoven RF, et al. Presented at ACR 2011; Poster #408.

Cited by Weinblatt ME. Clinical Symposium " Looking Ahead to Kinase Inhibition in
Rheumatoid Arthritis". Presented at ACR 2011.

Tofacitinib Phase 3

Monotherapy Study in RA

ACR20

DAS28
remission

Δ

HAQ

Placebo

28.3%

1.1%

-

0.24

Tofacitinib 5 mg

51.5%*

7.3%*

-

0.55*

Tofacitinib 10 mg

52.6%*

12.5%*

-

0.61*

Adalimumab

40 mg eow

47.2%*

6.2%*

-

0.49*

83

*
p
< 0.05 vs. placebo

van Vollenhoven RF, et al. Presented at ACR 2011; Poster #408.

Cited by Weinblatt ME. Clinical Symposium " Looking Ahead to Kinase Inhibition in
Rheumatoid Arthritis". Presented at ACR 2011.

Tofacitinib Phase 3

Monotherapy Study in RA

Treatment

group

Months 0
-
3

Months 3
-
6

AEs, n (%)

SAEs

, n
(%)

AEs, n (%)

SAEs

, n
(%)

Tofacitinib 5 mg BID (n=204)

106 (52.0)

12 (5.9)

67 (32.8)

10 (4.9)

Tofacitinib 10 mg BID
(n=201)

94 (46.8)

10 (5.0)

62 (30.8)

7 (3.5)

Adalimumab

40 mg SC Q2W
(n=204)

105 (51.5)

5 (2.5)

68 (33.3)

6 (2.9)

Placebo
(n=108 at mo. 3;
n=59 mos. 3
-
6)

51 (47.2)

2 (1.9)

16 (27.1)

2 (3.4)

Placebo to tofacitinib

5 mg
BID (n=28)

NA

NA

7 (25.0)

0

Placebo to tofacitinib

10 mg
BID (n=21)

NA

NA

9 (42.9)

0

84

van Vollenhoven RF, et al. Presented at ACR 2011; Poster #408.

Cited by Weinblatt ME. Clinical Symposium " Looking Ahead to Kinase Inhibition in
Rheumatoid Arthritis". Presented at ACR 2011.

What are the Potential Concerns with
Tofacitinib for the Clinician?


Decrease in neutrophil counts (1.5% severe
neutropenia with tofacitinib)


Decrease in hemoglobin


Significant elevation in serum creatinine
without clinical impact


Perturbation of lipid profile (↑HDL, ↑LDL)


Elevated liver enzymes


Placebo 17%, tofacitinib 28% (not proportional
to dosage)

van Vollenhoven RF, et al. Presented at ACR 2011; Poster #408.

Tofacitinib in RA: Open
-
Label, Long
-
Term
Extension Studies up to 36 Months

86

Data are for tofacitinib 5 mg or 10 mg groups combined (n=3227)

Wollenhaupt J, et al. Presented at ACR 2011; Poster #407.

Cited by Weinblatt ME. Clinical Symposium " Looking Ahead to Kinase Inhibition in
Rheumatoid Arthritis". Presented at ACR 2011.

71.0

72.7

47.3

52.3

26.3

35.2

0
10
20
30
40
50
60
70
80
Month 1
Month 36
% of patients with ACR responses

ACR20
ACR50
ACR70
Tofacitinib in RA: Open
-
Label, Long
-
Term
Extension Studies up to 36 Months


Mean tofacitinib exposure 309 days


Total 3118 patient years


Serious adverse events: 11.3/100 patient
-
years


↓ Hb


↑ ALT


↓ WBC


Creat. ↑ 33% in 12% of patients


Serious infectious events: 3.8/100 patient
-
years

87

n=3227,

Wollenhaupt J, et al. Presented at ACR 2011; Poster #407.

Cited by Weinblatt ME. Clinical Symposium " Looking Ahead to Kinase Inhibition in
Rheumatoid Arthritis". Presented at ACR 2011.

Fostamatinib (Oral SYK Inhibitor) for RA


Prodrug


Adverse effects are distinct from those of JAK
inhibition


Diarrhea


Headaches


↑ BP (controllable)


88

Weinblatt ME. Clinical Symposium " Looking Ahead to Kinase Inhibition in Rheumatoid
Arthritis". Presented at ACR 2011.

Fostamatinib Phase II Trials in RA

MTX
-
IR
1

MTX
-
IR
2

TNF
-
IR
3

100 BID
n=49

150 BID
n=47

150 qd

n=152

100 BID

n=152

100

BID
n=152

ACR20

Yes

Yes

Yes

Yes

No

ACR50

Yes

Yes

Yes

Yes

No

ACR70

Yes

Yes

No

Yes

No

DAS



NR

NR

Yes

Yes

No

DAS ≤ 2.6

NR

NR

Yes

Yes

No

HAQ



NR

NR

Yes

Yes

NR

↑ SF
-






ves

ves



X
-
ray inhibition

ND

ND

ND

ND

ND

% no progression

ND

ND

ND

ND

ND

ND = not done in the study; NR = not reported in the abstract

1. Weinblatt ME, et al. Presented at ACR 2008; Abstract #1189.

2. Weinblatt ME, et al. Presented at ACR 2009; Abstract #LB2.

3. Genovese MC, et al. Presented at ACR 2009; Abstract #LB3.

Cited by Fleischmann R. Clinical Symposium " Looking Ahead to Kinase Inhibition in
Rheumatoid Arthritis". Presented at ACR 2011.

VX
-
509 (Selective JAK3 Inhibitor) in RA:
Phase II Study

Placebo

(n=41)

VX
-
509


25
mg
BID

(n=41)

50
mg
BID

(n=41)

100
mg
BID

(n=40)

150
mg
BID

(n=41)

ACR20

29%

39%

61
%
*


65
%



66
%



ACR50

7.3%

17%

32
%



38
%
§

49
%
§


ACR70

2.4%

7.3%

12%

18
%
¥

22
%



Δ

aA匲8
-
䍒C

-
NK2

-
NKT

-
2KS
§


-
2.7
§


-
3.1
§


90

*
p
=0.007;

p
=0.002;

p
=0.011;
§
p
≤0.001
¥
p
=0.029

p
=0.026

Fleischmann R, et al. Presented at ACR 2011; Poster #L3

Safety of Kinase Inhibitors in RA

1. Tofacitinib phase II & III; 2. Fostamatinib phase II; 3. JAK 1/2 phase II.

Cited by Fleischmann R. Clinical Symposium " Looking Ahead to Kinase Inhibition in
Rheumatoid Arthritis". Presented at ACR 2011.

Tofacitinib
1

Fostamatinib
2

JAK

1/2
3

Number

of patients

3030

552

136

Neutropenia





Elevated lipids





Elevated

LFTs





↑ creatinine



Infection

(URI, UTI, flu)







Opportunistic infection







Herpes

Zoster



Diarrhea



Hypertension



Vertigo



Headache



Tofacitinib: What is Not Known in 2011


What is the optimal starting dose of tofacitinib?


Is 5 mg as effective as 10 mg?; Is 10 mg as safe as 5 mg?


Does tofacitinib require MTX to be effective?


Is the combination more effective than tofacitinib monotherapy?


In MTX naïve patients:


Is tofacitinib clinically the same as MTX or better?


Is tofacitinib more likely to inhibit radiographic progression?


If a patient fails to achieve a satisfactory response to 5 mg, will they
respond to 10 mg?


If a patient responds exceptionally well to 10 mg, will the patient
continue to respond to 5 mg?


If the patient goes into a true remission with tofacitinib, can it be
withdrawn and the patient maintain benefit?

Fleischmann R. Clinical Symposium " Looking Ahead to Kinase Inhibition in
Rheumatoid Arthritis". Presented at ACR 2011.

93

Imaging of Rheumatic Disease:
Ultrasonography and

Dual
-
emission X
-
ray
Absorptiometry


Highlights of an ACR Concurrent
Abstract Session, Sunday,
November 6

Summarized by Dr. Edith Villeneuve

List of Presentations in this Section

Speaker

Title

Abstract #

El Miedany YM

Imaging As An Outcome Measure in
Early Inflammatory Arthritis: Monitoring
Disease Activity and Patients’
oe獰on獥 to The牡p礠r獩ng
rlt牡獯nog牡phy

㠰8

vo獨i浩 o

rlt牡獯nog牡ph礠I猠a 偯tent Tool fo爠
偲mdi捴ion of lngoing 䩯int
ae獴牵捴ion au物ng Clini捡l oe浩獳son
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94

Concurrent Abstract Session:

Imaging of Rheumatic Disease. ACR 2011
;
Sun., Nov. 6.

Ultrasound As An Outcome Measure in Early
Arthritis: Study Design


Subjects
: 121 RA patients with sustained DAS28
remission for 6 months


65 on DMARDs, 56 on TNFi


Methods
:


Data Collected


PROMs (self
-
reported TJC)


US of 54 joints


GS 0
-
3, PD 0
-
3, score per joint and total
score


Treat
-
to
-
target of US remission (GS=0 and PD=0)


Post
-
tx correlation with clinical outcome
measures were assessed

El Miedany YM. Presented at ACR 2011; Presentation #808.

Clinical Outcome Measures

in Ultrasound
-
assessed 28 Joints

El Miedany YM. Presented at ACR 2011; Presentation #808.

NB: Results were similar for 28
-

and 44
-
joint assessments

Variable

US Findings

p

value

US arthritis

US remission

DAS
-
28

2.31 (0.2)

2.32 (0.2)

0.986

TJC 28 (Physician)

1.24 (0.4)

1.23 (0.4)

0.942

TJC 28 (Patient)

1.91 (0.6)

1.3 (0.6)

0.022

SJC 28

1.19 (0.4)

0 (0.0)

<0.001

PGA

11.9 (4.0)

9.6 (4.4)

0.028*

MS

10.7 (5.8)

8.1 (4.4)

0.021

Fn. Dis

0.56 (0.1)

0.73 (0.3)

<0.001

QoL

0.50 (0.1)

0.73 (0.5)

0.026

ESR

18.9 (5.2)

19.9 (6.9)

0.554

CRP

9.7 (3.6)

9.6 (3.2)

0.860

Ultrasound As An Outcome Measure in
Early Arthritis:
Results


US findings had an impact on management of
patients:


31.1% DMARD dose ↑


22% DMARD changed


21.6% biologic tx frequency ↑


52.6% of affected scan joint received IA
steroid


At subsequent visit, US improvement was
associated with clinical outcome measures in
response to treatment and helped maintained
pts in remission

El Miedany YM. Presented at ACR 2011; Presentation #808.

Ultrasound As An Outcome Measure in Early
Arthritis: Interpretation


These data suggest that US may be a better tool
to accurately evaluate clinical remission and
may provide better treatment / outcomes for
patients


However, more stringent definition of remission
is now recommended as the target


Still need to demonstrate:


Using US would have changed management


Long
-
term outcomes of using US remission
as target compared to clinical remission

El Miedany YM. Presented at ACR 2011; Presentation #808.

Ultrasound As a Tool for Prediction of Ongoing

Joint Destruction During Clinical Remission of RA


Objective
: To assess whether US of 22 joints can
predict long
-
term radiographic progression during
sustained clinical DAS28 remission


Subjects
:
RA patients from a single outpatient
clinics who fulfilled criteria of clinical remission


DAS28
-
ESR < 2.6
or


DAS28
-
CRP < 2.3


Methods
:


US performed by rheumatologists blind to the
clinical findings


Hand X
-
ray films assessed using modified total
Sharp score (mTSS) by a rheumatologist unaware
of the US findings


Yoshimi R. Presented at ACR 2011; Presentation #809.

Ultrasound for Prediction of Ongoing

Joint Destruction: US Assessment

Yoshimi R. Presented at ACR 2011; Presentation #809.


PD signals of 22 joints


Each joint scored

Grade 0
-
3)


Total PD score =

Sum of PD scores

of all 22 joints


Ultrasound for Prediction of Ongoing Joint
Destruction: Patient Characteristics

Characteristic

Total no. of cases = 31

Age

55.2
±

13.4 years

Sex

M: 4 cases F: 27 cases

Stage


: 9 捡獥猬

: 15 cases,

: 3 cases,

: 4 cases

RF

(+): 23 cases, (
-
): 4 cases, Unknown: 4 cases

Duration of RA

Median 5 y 0 m (2 y 6 m


16 y)

Duration of remission

Median 1 y 4 m (2 m


6 y 5 m)

DAS28
-
ESR

2.06
±

0.63

DAS28
-
CRP

1.58
±

0.47

Treatment

Biologics: 13 cases (IFX 4, ETA 9)

DMARDs: 28 cases (MTX 23, SSZ 6, TAC 1)

Steroid: 9 cases (PSL 1
-

5 mg/d)

Drug
-
free: 1 case

Yoshimi R. Presented at ACR 2011; Presentation #809.

Ultrasound for Prediction of Ongoing Joint
Destruction: Patient Disposition

Yoshimi R. Presented at ACR 2011; Presentation #809.

Ultrasound for Prediction of Ongoing Joint Destruction:
Radiographic Progression & Baseline Parameters

Variable

No radiographic

progression

Radiographic

progression

P value

Total PD score

0.87
±

1.15

6.00
±

6.44

0.0099

Total gray score

8.80
±

5.78

12.6
±

12.4

0.36

SJC

0.33
±

0.79

1.29
±

0.70

0.017

TJC

0.13
±

0.34

0.57
±

0.49

0.032

gVAS (mm)

9.40
±

9.58

12.7
±

4.40

0.41

ESR (mm/h)

10.2
±

5.94

18.6
±

16.2

0.11

CRP (mg/dl)

0.12
±

0.15

0.08
±

0.12

0.60

MMP
-
3 (ng/ml)

96.8
±

110

62.1
±

19.7

0.44

RF (U/ml)

73.8
±
89.5

86.8
±

68.1

0.77

*

No difference for age, disease duration, remission duration, MTX dose, Treatment
between the 2 groups

Yoshimi R. Presented at ACR 2011; Presentation #809.

Total PD Score & Radiographic
Progression

0
3
6
9
0
1
2
3
4
≥5

No. of patients

Total PD Score

No radiographic progression
Radiographic progression

X
-
ray progression is
strongly associated
with total PD score but
also with TJC and SJC


X
-
ray progression was
not found in patients
having total PD score
of 0 or 1



Yoshimi R. Presented at ACR 2011; Presentation #809.

Ultrasound for Prediction of Ongoing Joint
Destruction: Interpretation


NPV of total PD score of 0 and 1 is very
interesting


Added value of PD > 1 in an individual patients
still needs to be determined:


Does is it add to physical exam?


How do you differentiate a progressor from a
non
-
progressor in an individual patient?

Yoshimi R. Presented at ACR 2011; Presentation #809.


106

Discovery 2011

Highlights of an ACR Plenary
Session, Sunday, November 6

Summarized by Dr. Robert Offer

Presentation in this Section

Speaker

Title

Abstract #

Bozaite
-
Gluosniene R

Reduced Cardiovascular Risk with Use
of Methotrexate and Tumor Necrosis
Factor
-
α Inhibitors in Patients with
Rheumatoid Arthritis

719

107

Plenary Session: Discovery 2011. ACR 2011
;
Sun., Nov. 6.

Impact of MTX + TNFi Treatment on
Cardiovascular Risk in RA


Design
: RA inception cohort using electronic
health records


Subjects
: 1718 RA patients without history of
CVD


Primary outcome
: Incident CVD, including any o
the following:


Coronary artery disease (CAD)


Cardiac or arterial revasc. procedure


Stroke / TIA


Abdominal aortic aneurysm


Peripheral artery disease



Bozaite
-
Gluosniene R. Presented at ACR 2011; Presentation #719.

Impact of MTX + TNFi Treatment on
Cardiovascular Risk in RA: Co
-
variates

Category

Co
-
variates

Demographics

Age, gender, ethnicity

Comorbidities

BMI (kg/m2), SBP/DBP, HTN, hyperlipidemia,
diabetes

Laboratory measures

ESR, CRP, LDL, RF, anti
-
CCP antibodies

Medications

NSAIDs, glucocorticoids, hydroxychloroquine,
MTX, TNF
-
α
inhibitors, statins

Propensity score (by
multivariate regression
models)

For probability of a patient taking MTX or
TNF
-
α inhibitor


Bozaite
-
Gluosniene R. Presented at ACR 2011; Presentation #719.

Risk of Developing CVD by

Cumulative TNF
-
α Inhibitor Use

Never

≤ 17 mo

>17 mo

No. of
patients

1147

286

285

No. of CVD events

102

16

9

HR*

(95% CI)

1.04

(0.57
-
1.88)

0.31

(0.15
-
0.63)

*

Adjusted for propensity score, age, gender, race, propensity score, body mass
index, history of hypertension, hyperlipidemia and diabetes, ESR, CRP, RF and anti
CCP antibodies and use of NSAIDs, glucocorticoids, HCQ and MTX

Bozaite
-
Gluosniene R. Presented at ACR 2011; Presentation #719.

Risk of Developing CVD by

Cumulative Methotrexate Use

Never

≤ 22 mo

> 22 mo

No. of
patients

652

532

534

No. of CVD events

70

35

22

HR*

(95% CI)

1.15

(0.71
-
1.86)


0.28

(0.16
-
0.49)


*

Adjusted for age, gender, race, propensity score, body mass index, history of
hypertension, hyperlipidemia and diabetes, ESR, CRP, RF and anti
-
CCP antibodies,
and use of glucocorticoids, HCQ, TNF
-
α
inhibitors, and NSAIDs

Bozaite
-
Gluosniene R. Presented at ACR 2011; Presentation #719.

Impact of MTX + TNFi Treatment on
Cardiovascular Risk in RA: Conclusions


In this inception RA cohort, use of MTX >22 months
was independently associated with a 72% reduction
in risk of incident CVD


Use of TNF
-
α inhibitors >17 months was
independently associated with a 69% reduction in
risk of incident CVD


The findings are biologically plausible, given the
role of inflammation in atherosclerosis and the
potent anti
-
inflammatory effects of these
medications that may take several months to
manifest their effect


These findings suggest that these medications are
protective against CVD in a group of patients at
high risk for CVD


Bozaite
-
Gluosniene R. Presented at ACR 2011; Presentation #719.

113

Late
-
breaking Abstracts

Highlights of an ACR Concurrent
Abstract Session, Tuesday,
November 8

Summarized by Dr. Janet Pope

List of Presentations in this Section

Speaker /
primary author

Title

Abstract #

Burmester GR

Mavrilimumab (an Anti
-
GM
-
CSFR
α
Monoclonal
Antibody) in Subjects with Rheumatoid Arthritis:
Results of a Phase 2 Randomized, Double
-
Blind,
Placebo
-
Controlled Study

L7

Genovese M

Sarilumab for the Treatment of Moderate
-
to
-
Severe Rheumatoid Arthritis: Results of a Phase
2, Randomized, Double
-
Blind, Placebo
-
Controlled,
International Study

L2

Tak PP

Safety and Efficacy of Oral Chemokine Receptor 1
Antagonist CCX354
-
C in a Phase 2 Rheumatoid
Arthritis Study

L11

114

Concurrent abstract session
:

Late
-
breaking abstracts. ACR
2011;

Tues., Nov. 8.

List of Presentations in this Section (cont'd)

Speaker /
primary author

Title

Abstract #

Becker

LM

BCX4208 Combined with Allopurinol Increases
Response Rates in Patients with Gout Who Fail to
Reach Goal Range Serum Urate on Allopurinol
Alone: A Randomized, Double
-
Blind, Placebo
-
Controlled Trial

L10

Ko VW

Is Centre
-
Based Rehabilitation Superior to Home
-
Based Rehabilitation After Knee Replacement? A
Single
-
Blind, Randomised Controlled Trial

L6

Brown JP

Six Years of Denosumab Treatment in
Postmenopausal Women with
Osteoporosis:


Results From the First Three Years
of the FREEDOM Extension

L8

115

Concurrent abstract session
:

Late
-
breaking abstracts. ACR
2011;

Tues., Nov. 8.

Mavrilimumab for RA: Phase 2 Study


Subjects
: 264 patients from Eastern Europe &
Japan) with moderate
-
to
-
severe RA


Stable MTX ≥ 4 wks prior to screening


DAS28 ≥ 3.2 at screening


Randomization
: 2:1 active/placebo


Primary endpoint
: DAS28
-
CRP decrease >1.2 from
baseline at week 12


Secondary endpoints
:


DAS28
-
CRP remission


ACR20/50/70


HAQ
-
DI


Safety profile

116

Burmester GR. Presented at ACR 2011; Presentation #L7.

Response

Mavrilimumab for RA: Time to Onset of
DAS28 Response & Remission

Response

Remission

117

Burmester GR. Presented at ACR 2011; Presentation #L7.

Remission

Mavrilimumab for RA:

ACR20, 50 & 70 at Day 85

118

Burmester GR. Presented at ACR 2011; Presentation #L7.

Mavrilimumab for RA:

ACR50 and 70 By Visit

ACR50

ACR50

ACR70

ACR70

119

Burmester GR. Presented at ACR 2011; Presentation #L7.

Mavrilimumab for RA: Conclusions

from a Phase 2 Study


Mavrilimumab was associated with:


A rapid (within 2 wks) and significant clinical
effect compared with placebo


A safety profile over the first 3 months of dosing
that had no reported serious and opportunistic
infections, hypersensitivity reactions,
anaphylaxis, clinically meaningful adverse events,
or laboratory abnormalities up to the highest dose
tested


The results from this study suggest that
suppressing macrophage activity by targeting GM
-
CSFRα may be a novel approach in the treatment of
RA and supports future clinical studies

120

Burmester GR. Presented at ACR 2011; Presentation #L7.

Sarilumab for Moderate
-
to
-
Severe RA:

Phase 2 Study


Sarilumab = fully human monoclonal antibody
directed against IL
-
6Rα


Objective
: To evaluate the efficacy and safety

of 5
dose regimens of subcutaneous sarilumab vs.
placebo (both with MTX) in RA


Subjects
: 306 adults with active, moderate
-
to
-
severe RA with inadequate response to MTX


Method
: 12
-
week double
-
blind trial


Subjects randomized to sarilumab 100 mg q2w,
150 mg q2w, 100 mg qw, 200 mg q2w, 150 mg qw,
or placebo


Primary endpoint: % achieving ACR20 at Week 12

Genovese MC, et al. Presented at ACR 2011; Presentation #L2.

Sarilumab for Moderate
-
to
-
Severe RA:

Phase 2 Study

Genovese MC, et al. Presented at ACR 2011; Presentation #L2.

0
10
20
30
40
50
60
70
80
Placebo
100 mg
q2w
150 mg
q2w
100 mg qw
200 mg
q2w
150 mg qw
% achieving ACR responses

ACR20
ACR50
ACR70
Sarilumab dose

Oral Chemokine Receptor 1 Antagonist
CCX354
-
C in RA: Phase 2 Study


Objective
: To evaluate safety, tolerability and efficacy of
CCX354
-
C in subjects with RA with inadequate response to
MTX


Subjects:
160 adult subjects with RA, on stable dose of MTX


≥ 8 SJC, 8 TJC (based on 66/68 joint count)


CRP > 5 mg/L


Methods:

Randomized, 12
-
week double
-
blind, placebo
-
controlled, parallel group


Stratification based on previous biologics use, and current
corticosteroid use


Randomized to placebo, CCX354
-
C 100 mg bid or 200 mg qd


Efficacy measures: ACR, DAS28, CRP, ESR, bone turnover
markers

Tak PP. Presented at ACR 2011; Presentation #L11.

Oral Chemokine Receptor 1 Antagonist
CCX354
-
C in RA: Phase 2 Study

ACR20 at Week 12

Placebo

100 mg
BID

200 mg
QD

P
-
value

ITT, Day 1 Eligible
Subjects

30%

44%

56%

0.014

ITT, Including Day 1
Ineligible Subjects

39%

43%

52%

0.17

Biologic
-
naïve

35%

42%

57%

0.059

Day 1 Eligible,
Biologics
-
naïve

27%

42%

62%

0.002

Tak PP. Presented at ACR 2011; Presentation #L11.

BCX4208 Combined with Allopurinol in Gout


BCX4208 = Purine nucleoside phosphorylase
(PNP) inhibitor


Objective
: To evaluate BCX4208 therapy added
on to allopurinol 300mg in allopurinol
inadequate responders


Subjects:

279 patients with gout


Baseline sUA ≥ 6.0 mg/dL after 2 weeks on
300mg of allopurinol


Methods
:


Primary endpoint: % patients with sUA <
6mg/dL at week 12


Long
-
term extension is ongoing



Becker LM. Presented at ACR 2011; Presentation #L10.

BCX4208 Combined with Allopurinol in Gout:
Primary Efficacy Results

18%

45
%*

33%

39
%*

49
%


0%
10%
20%
30%
40%
50%
60%
Placebo
5 mg
10 mg
20 mg
40 mg
% achieving

sUA < 6mg/dL at week 12


*
p
<0.05;

p
<0.001


Becker LM. Presented at ACR 2011; Presentation #L10.

BCX4208 dose

Centre
-
based vs. Home
-
based Rehabilitation
After Knee Replacement: Single
-
Blind RCT


Subjects
: 249 patients requiring supervised
physical therapy after total knee replacement


Methods
:


Two
-
weeks post
-
surgery, subjects
randomized to:


12 sessions of 1
-
to
-
1 therapy


12 sessions of group based therapy


Home exercises supplemented with two 1
-
to
-
1 sessions and a telephone follow
-
up


Results
: Supervised outpatient sessions are not
superior to a monitored home programme after
TKR

Ko VW, et al. Presented at ACR 2011; Poster #L6.

Denosumab for Postmenopausal Women with
Osteoporosis:

6
-
year Results from the FREEDOM Extension


Objectives
: To describe the effects of up to 6
years of denosumab treatment on:


Bone turnover and bone density


Safety: incidence of new vertebral and
nonvertebral fractures, incidence of adverse
events


Subjects
:


2,207 patients crossed over from placebo to
denosumab after double
-
blind period


2,343 patients treated with long
-
term
denosumab from the start of the trial

Brown JP. Presented at ACR 2011; Presentation #L8.

Denosumab for Postmenopausal Women with Osteoporosis:
% Change in BMD at the Lumbar Spine and Total Hip

*
p

< 0.05 vs FREEDOM baseline;

p

< 0.0001 vs FREEDOM and extension baseline.
Brown JP. Presented at ACR 2011; Presentation #L8.

Denosumab for Postmenopausal Women with Osteoporosis:
Conclusions from the FREEDOM Extension Study

*
p

< 0.05 vs FREEDOM baseline;

p

< 0.0001 vs FREEDOM and extension baseline.
Brown JP. Presented at ACR 2011; Presentation #L8.


Denosumab treatment for 6 years (long
-
term
group):


Maintained the reduction in bone turnover


Continued to significantly increase BMD year
to year


Was associated with low incidences of new
vertebral and nonvertebral fractures


Remained well tolerated


Denosumab treatment for 3 years (cross
-
over
group) largely reproduced the observations in
the original FREEDOM denosumab group

131

Spondylarthropathies:

Recent Insights

Highlights of an ACR Clinical
Symposium,

Tuesday, November 8

Summarized by Dr. Majed Khraishi

List of Presentations in this Section

Speaker / primary
author

Title

Abstract

#

Maksymowych

WP

TNF Inhibition and Structural
Progression in Ankylosing
Spondylitis

NA

Kingsley GH

Is Methotrexate a Disease Modifying
Agent in Psoriatic Arthritis?

NA

Khraishi M

Analysis of Radiographic Changes in
Patients with Early Psoriatic Arthritis

1548

132

Clinical Symposium:

Spondylarthropathies: Recent Insights. ACR 2011
;
Tues., Nov. 8.

Hypothesis: Inflammation and Ankylosis

Are Uncoupled in AS Pathogenesis

Lories RJ, et al: Arthritis Rheum 2007; 56(2):489
-
97.


Cited by Maksymowych WP. Clinical Symposium " Spondylarthropathies: Recent Insights".

Presented at ACR 2011.

Hypothesis: Pathogenesis

of New Bone in Ankylosing Spondylitis

Maksymowych WP. Clinical Symposium " Spondylarthropathies: Recent Insights".

Presented at ACR 2011.

Evidence for Methotrexate in PsA:

Observations from the NOR
-
DMARD Registry

Lie E, et al. Ann Rheum Dis. 2010; 69(4):671
-
6.

Cited by Kingsley GH. Clinical Symposium " Spondylarthropathies: Recent Insights".

Presented at ACR 2011.


After 6 months MTX


PsA and RA patients show improvements in most
disease activity measures and patient reported
outcomes


In adjusted analysis less improvement with PsA, but
changes in same range as RA


EULAR good/moderate responses were achieved by
24%/57% PsA and 33%/70% RA


At 2 years


Retention rates on MTX were 65% PsA and 66% RA


Only minor differences in reasons for discontinuation

Evidence for Methotrexate in PsA:

MTX in Psoriatic Arthritis (MIPA) Trial


Hypothesis
: MTX improves disease activity and function
in psoriatic arthritis


Design
: 6
-
month RCT comparing MTX with placebo


Inclusion criteria
: Synovitis in ≥ 1 joint, psoriasis
skin/nails


Exclusion criteria
: Other arthropathies, recent
steroids/DMARDs, contra
-
indications to MTX


Interventions
: MTX (target 15mg/wk) or placebo


Primary outcome
: Psoriatic Arthritis Response Criteria


Secondary outcomes
: Patient & assessor global
assessments, HAQ & Pain, TJC, SJC, ESR, CRP,
composite measures

Kingsley GH