Transcript Communications

ACR 2011 Medical Passport
Highlights of ACR 2011
Chicago, IL
November 2011
1
Faculty
Hector Arbillaga, MD
Peter Panopalis, MD
Philip Baer, MD
Janet Pope, MD
Majed Khraishi, MD
Anthony Russell, MD
Clode Lessard, MD
Yves Troyanov, MD
Robert Offer, MD
Edith Villeneuve, MD
Medical Passport Program-ACR 2011
2
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
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product monograph.
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Outline
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
Majed Khraishi, MD
RA Treatment: Small Molecules, Biologics
and Gene Therapy
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:
Philip Baer, MD
Clinical Aspects and Pathogenesis
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
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
Janet Pope, MD
6
RA Treatment: Existing Diseasemodifying Antirheumatic Drugs
and Corticosteroids
Highlights of the ACR Concurrent
Abstract Session held Tuesday,
November 8
Summarized by Dr. Hector Arbillaga
7
List of Presentations in this Section
Speaker
Title
Villeneuve E
Preliminary Results of a Multicentre
Randomised Controlled Trial of
Etanercept and Methotrexate to Induce
Remission in Patients with Newly
Diagnosed Inflammatory Arthritis
Concurrent Abstract Session—RA Treatment: Existing Disease-modifying
Antirheumatic Drugs and Corticosteroids. ACR 2011; Tues., Nov. 8.
Abstract #
2465
8
MTX + Etanercept or Placebo in RA:
Design of The EMPIRE Study
Villeneuve E, et al. Presented at ACR 2011; Presentation #2465.
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MTX + Etanercept or Placebo in RA:
Clinical Remission* in the EMPIRE Study
MTX + placebo
MTX + etanercept
p = ns
35
% of patients
30
p = ns
29
31
24
25
20
15
p = 0.051
16
11
10
5
2
0
Week 2
Week 26
*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.
Week 52
10
Does the Presence of ACPA Impact on Efficacy?
DAS28 Remission at Week 52 (EMPIRE Study)
Villeneuve E, et al. Presented at ACR 2011; Presentation #2465.
11
MTX + Etanercept or Placebo in RA:
Conclusions from the EMPIRE Study
• 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
Villeneuve E, et al. Presented at ACR 2011; Presentation #2465.
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Rheumatoid Arthritis:
Clinical Aspects
Highlights of ACR Poster and
Concurrent Abstract Sessions,
Sunday November 6
Summarized by Drs. Robert Offer and
Peter Panopalis
13
List of Presentations in this Section
Speaker / Primary
Author
Title
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 DiseaseNaïve Patients with Rheumatoid Arthritis
759
Poster and Concurrent Abstract Sessions:
Rheumatoid Arthritis: Clinical Aspects. ACR 2011; Sun., Nov. 6
Abstract #
14
List of Presentations in this Section (cont'd)
Speaker / Primary
Author
Title
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
Poster and Concurrent Abstract Sessions:
Rheumatoid Arthritis: Clinical Aspects. ACR 2011; Sun., Nov. 6
Abstract #
15
List of Presentations in this Section (cont'd)
Speaker / Primary
Author
Title
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
Poster and Concurrent Abstract Sessions:
Rheumatoid Arthritis: Clinical Aspects. ACR 2011; Sun., Nov. 6
Abstract #
16
Prolonged Hydroxychloroquine Use in RA
is Associated with Decrease in CVD
72% reduction
p<0.001 vs.
never use
Bili A, et al. Presented at ACR 2011; Poster #1168.
Prolonged Hydroxychloroquine Use in RA
is Associated with Decrease in CAD
73% reduction
p<0.001 vs.
never use
Bili A, et al. Presented at ACR 2011; Poster #1168.
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
80
% of affected segments
70
p = 0.0002
Controls
RA
70
60
51
50
p = 0.004
40
28
30
21
20
14
16
10
0
Non-calcified
Mixed
Karpouzas GA, et al. Presented at ACR 2011; Presentation #759.
Full calcified
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), interadventitial 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 patients1,3
• 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 RA2
• 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
criteria2
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 arthritis1
 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
similarly2
• 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 set3
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.
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The Use of RAPID3 for a
Treat-to-Target Strategy
• Background: RAPID3 is a composite measure
of disease activity, requiring only 3 patient selfreported 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
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
N•
=4479
•
Yokogawa N, et al. Presented at ACR 2011; Presentation #345.
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
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List of Presentations in this Section
Speaker
Title
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
Poster Session: Clinical Features of Rheumatoid Arthritis; Disease Severity;
Outcomes Research and Metrology. ACR 2011; Tues., Nov. 8.
Abstract #
29
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*
Ineffective
No method
Use in this cohort†
36 (34%)
85%
Abstinence
16
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
0.2%
4
Intra-uterine device
Sterilization
*% 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.
46 (43.4%)
FDA Pregnancy Categories: RA Medications
FDA
Definition
Category
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
Clowse ME, et al. Presented at ACR 2011; Poster #2109.
Methotrexate
Leflunomide
Contraceptive Use by RA Medication
Class
B
Class
C
Class
X
Contraception
Women
taking
medication
Ineffective
Effective
Sterilization
TNFi
56 (53%)
23 (41%)
14 (25%)
19 (34%)
SSZ
6 (6%)
1 (17%)
2 (33%)
3 (50%)
HCQ
20 (19%)
6 (30%)
7 (35%)
7 (35%)
ABA or
RTX
13 (12%)
3 (23%)
0
10 (77%)
MTX or
LEF
59 (56%)
17 (28%)
14 (23%)
28 (48%)
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.
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
35
List of Presentations in this Section
Speaker /
primary author
Title
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
Poster Sessions—RA Treatment: Small Molecules, Biologics
and Gene Therapy. ACR 2011; Nov. 6-8.
Abstract #
36
List of Presentations in this Section (cont'd)
Speaker /
primary author
Title
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 Biologicnaïve 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
Poster Sessions—RA Treatment: Small Molecules, Biologics
and Gene Therapy. ACR 2011; Nov. 6-8.
Abstract #
37
List of Presentations in this Section (cont'd)
Speaker
Title
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 FactorInhibitors: 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
Poster Sessions—RA Treatment: Small Molecules, Biologics
and Gene Therapy. ACR 2011; Nov. 6-8.
Abstract #
38
List of Presentations in this Section (cont'd)
Speaker
Title
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
Poster Sessions—RA Treatment: Small Molecules, Biologics
and Gene Therapy. ACR 2011; Nov. 6-8.
Abstract #
39
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 multicentre 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: To 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. nonexposed patients
Pope J, et al. Presented at ACR 2011; Poster #1222.
Abatacept in Real-World Practice:
Baseline Characteristics and Disposition
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
Mild
1 (0.27)
4 (0.29)
5 (0.28)
Moderate
22 (5.96)
104 (7.42)
126 (7.11)
Parameter
Disease
Severity,
n (%)
0.736
Severe
346 (93.77)
1,291 (92.08)
1,637 (92.43)
NA
0 (0.00)
3 (0.21)
3 (0.17)
26.12 (0.86)
25.75 (0.58)
26.79 (0.53)
Mean durability of
treatment, months (SD)
Pope J, et al. Presented at ACR 2011; Poster #1222.
< 0.001
Abatacept in Real-World Practice:
Change in HAQ Scores
2
1.8
Mean HAQ Score
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
Post DMARD
Post TNFi
Total cohort
0
Baseline
12 months
Pope J, et al. Presented at ACR 2011; Poster #1222.
24 months
36 months
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
MCID
Yes, n
(%)
No, n
(%)
# of prior
biologics
0
≥1
213
(70.1)
806
(71.4)
91
(29.9)
323
(28.6)
OR
95%
CI
p
value
NNT
(1/ARR)
Modified
NNT 0
biologics
Modified
NNT ≥ 1
biologic
0.94
0.71
to
1.24
0.65
75.5
1.43
1.40
Pope J, et al. Presented at ACR 2011; Poster #1222.
Abatacept in Real-World Practice:
Conclusions
• Abatacept 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.
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
48
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
49
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 selfreported 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
50
RAPID3 component scores at baseline
Adapted from Yazici et al. ACR 2011
51
Cumulative incidence of time to RAPID3 >3.6
response adjusted for age and disease duration
Adapted from Yazici et al. ACR 2011
52
Conclusion
Overall 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.
53
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, %
66.7
59.3
54.9
Good EULAR response, %
73.5
83.3
72.1
TSS 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
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
Emery P, et al. Presented at ACR 2011; Poster #429.
Direct Comparison of 4 Biologics
in Biologic-Naïve RA Patients
• 144 biologic-naïve patients starting a biologic
from July 2008 onward
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
6.6
6.3
5.3
6.2
<0.01
84
67
74
59
0.11
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
MTX dosage, mg/wk
Concomitant PSL, %
PSL dosage, mg/day
Yonemoto Y, et al. Presented at ACR 2011; Poster #1236.
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 results1
• Slightly better response of TCZ group possibly due
to suppression of APR1
 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 monotherapy2
– 8 years of adalimumab ± MTX3
– 2 years of abatacept in a real-world setting4
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
507
1.6*
1.2 to 2.2
1.7*
1.3 to 2.2
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
Infliximab
Adalimumab
*Statistically significant difference vs. DMARD group
Strangfeld A, et al. Presented at ACR 2011; Poster #461.
Fatigue: Are All Biologics Equal?
7
Mean level of fatigue
DMARD
Etanercept
6
Infliximab
Adalimumab
Rituximab
5
Abatacept
Tocilizumab
4
Baseline
3 months
Strangfeld A, et al. Presented at ACR 2011; Poster #461.
6 months
Real-life Biologic Switching Patterns
• Among patients on a 2nd 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 3rd biologic
within 1 year
 23.3% of 2nd-line anti-TNF patients switched to a
3rd agent
 15.9% of 2nd-line abatacept patients switched to a
3rd agent
Analysis of pharmacy data in the US
Meissner B, et al. Presented at ACR 2011; Poster #2198.
61
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
66 (100)
66 (100)
132 (99.2)*
132 (98.5)†
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)
Prior TNFi
Adalimumab
Certolizumab
Etanercept
Golimumab
Infliximab
*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
60
48.1†
50
% of patients
41.7*
40
30
24.4
20
10
0
Placebo
Tofacitinib 5 mg
*p≤0.05; †p<0.0001
Burmester JR, et al. Presented at ACR 2011; Presentation #718.
Tofacitinib 10 mg
Tofacitinib in TNF Failures: ACR20 Responses
at Month 3 by Previous TNFi Exposure
Placebo
Tofacitinib 5 mg
60
Tofacitinib 10 mg
53.3†
48.3
50
% of patients
43.4*
41.7
37.8*
40
36.4
30.6
30
22.2
20
10.8
10
0
1 Prior TNFi
2 Prior TNFis
*p≤0.05; †p<0.0001
Burmester JR, et al. Presented at ACR 2011; Presentation #718.
3 Prior TNFis
Tofacitinib in TNF Failures: Laboratory Tests
Month 3
PBO
Month 6
5 mg
BID
10 mg
BID
PBO
5
PBO
 10
5 mg
BID
10 mg
BID
LS mean change from baseline
Neutrophil count, 103/mm3
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 from baseline, %
-0.3
11.1†
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/mm3)
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
Yamanaka H, et al. Presented at ACR 2011; Poster #1215.
68
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
Vanhoutte F, et al. Presented at ACR 2011; Poster #2210.
69
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 abatacept2
 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.
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
71
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?
Clinical Symposium: Looking Ahead to Kinase Inhibition in Rheumatoid Arthritis
ACR 2011; Sun., Nov. 6 25.
72
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
Genovese MC. Clinical Symposium " Looking Ahead to Kinase Inhibition in
Rheumatoid Arthritis". Presented at ACR 2011.
73
JAK Signalling
JAK1
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/β
Type 1 interferons
α/β
Type II interferons γ
Type II interferons γ
Genovese MC. Clinical Symposium " Looking Ahead to Kinase Inhibition in
Rheumatoid Arthritis". Presented at ACR 2011.
74
Other Enzymes: SYK and BTK
Enzyme
Pathway
Spleen tyrosine kinase (SYK)
FcγR and B-cell receptor signalling
Bruton’s Tyrosine Kinase (BTK)
Activated by SYK
Genovese MC. Clinical Symposium " Looking Ahead to Kinase Inhibition in
Rheumatoid Arthritis". Presented at ACR 2011.
75
Tofacitinib (JAK Inhibitor): 6-week Phase II
Study in RA in Monotherapy
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.
76
Tofacitinib (JAK Inhibitor): Phase II Study in RA
in Combination with MTX – Week 12 Results
% of patients with ACR responses
ACR20
ACR50
ACR70
70
60.6
60
58.7
60.0
50
40
37.7
30
20
10
0
Placebo + MTX
5 mg + MTX
15 mg + MTX
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.
20 mg + MTX
77
Tofacitinib (JAK Inhibitor): Phase II Study
in RA in Monotherapy – Week 12 Results
% of patients with ACR responses
ACR20
80
ACR50
75.4
70
ACR70
75.4
63.3
60
47.2
50
40
30
28.8
20
10
0
Placebo
Tofacitinib 5 Tofacitinib 10 Tofacitinib 15 Adalimumab
mg
mg
mg
40 mg eow
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.
78
Tofacitinib (JAK Inhibitor): Phase III Study
in RA in Monotherapy – Week 12 Results
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%
*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.
79
Tofacitinib (JAK Inhibitor): Phase III Study in RA in
Combination with DMARDs – Week 24 Results
ACR20
Δ HAQ
DAS Remission
Placebo
31%
-0.21
3%
5 mg bid
53%*
-0.46*
11%
10 mg bid
58%*
-0.56*
15%*
*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.
80
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
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.
81
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  tofacitinib 5 mg BID SC Q2W; or
 Placebo  tofacitinib 10 mg BID SC Q2W
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.
82
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*
*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.
83
Tofacitinib Phase 3
Monotherapy Study in RA
Months 0-3
Treatment group
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
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.
84
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
% of patients with ACR responses
ACR20
80
ACR50
ACR70
72.7
71.0
70
60
50
52.3
47.3
40
35.2
26.3
30
20
10
0
Month 1
Month 36
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.
86
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
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.
87
Fostamatinib (Oral SYK Inhibitor) for RA
• Prodrug
• Adverse effects are distinct from those of JAK
inhibition
 Diarrhea
 Headaches
 ↑ BP (controllable)
Weinblatt ME. Clinical Symposium " Looking Ahead to Kinase Inhibition in Rheumatoid
Arthritis". Presented at ACR 2011.
88
Fostamatinib Phase II Trials in RA
MTX-IR1
MTX-IR2
TNF-IR3
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-36
NR
NR
Yes
Yes
NR
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
VX-509
Placebo
(n=41)
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 DAS28-CRP
-1.2
-1.7
-2.6§
-2.7§
-3.1§
*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
90
Safety of Kinase Inhibitors in RA
Tofacitinib1
Fostamatinib2
JAK 1/23
3030
552
136
Neutropenia


Elevated lipids

Elevated LFTs

↑ creatinine

Infection (URI, UTI, flu)



Opportunistic infection



Herpes Zoster

Number of patients


Diarrhea

Hypertension

Vertigo

Headache
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: 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.
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
93
List of Presentations in this Section
Speaker
Title
El Miedany YM
Imaging As An Outcome Measure in
Early Inflammatory Arthritis: Monitoring
Disease Activity and Patients’
Response to Therapy Using
Ultrasonography
808
Yoshimi R
Ultrasonography Is a Potent Tool for
Prediction of Ongoing Joint
Destruction During Clinical Remission
of Rheumatoid Arthritis
809
Concurrent Abstract Session:
Imaging of Rheumatic Disease. ACR 2011; Sun., Nov. 6.
Abstract #
94
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
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
NB: Results were similar for 28- and 44-joint assessments
El Miedany YM. Presented at ACR 2011; Presentation #808.
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
• PD signals of 22 joints
• Each joint scored
Grade 0-3)
• Total PD score =
Sum of PD scores
of all 22 joints
Yoshimi R. Presented at ACR 2011; Presentation #809.
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
Ⅰ: 9 cases, Ⅱ: 15 cases, Ⅲ: 3 cases, Ⅳ: 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
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
Variable
* 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
No radiographic progression
Radiographic progression
No. of patients
9
• 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
6
3
0
0
1
2
3
4
Total PD Score
≥5
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.
Discovery 2011
Highlights of an ACR Plenary
Session, Sunday, November 6
Summarized by Dr. Robert Offer
106
Presentation in this Section
Speaker
Title
BozaiteGluosniene R
Reduced Cardiovascular Risk with Use
of Methotrexate and Tumor Necrosis
Factor-α Inhibitors in Patients with
Rheumatoid Arthritis
Plenary Session: Discovery 2011. ACR 2011; Sun., Nov. 6.
Abstract #
719
107
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
1.04
(0.57-1.88)
0.31
(0.15-0.63)
HR*
(95% CI)
* 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.
Late-breaking Abstracts
Highlights of an ACR Concurrent
Abstract Session, Tuesday,
November 8
Summarized by Dr. Janet Pope
113
List of Presentations in this Section
Speaker /
primary author
Title
Burmester GR
Mavrilimumab (an Anti-GM-CSFRα 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-toSevere 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
Concurrent abstract session:
Late-breaking abstracts. ACR 2011; Tues., Nov. 8.
Abstract #
114
List of Presentations in this Section (cont'd)
Speaker /
primary author
Title
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, PlaceboControlled Trial
L10
Ko VW
Is Centre-Based Rehabilitation Superior to HomeBased 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
Concurrent abstract session:
Late-breaking abstracts. ACR 2011; Tues., Nov. 8.
Abstract #
115
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
Burmester GR. Presented at ACR 2011; Presentation #L7.
116
Mavrilimumab for RA: Time to Onset of
DAS28 Response & Remission
Response
Remission
Response
Remission
Burmester GR. Presented at ACR 2011; Presentation #L7.
117
Mavrilimumab for RA:
ACR20, 50 & 70 at Day 85
Burmester GR. Presented at ACR 2011; Presentation #L7.
118
Mavrilimumab for RA:
ACR50 and 70 By Visit
ACR50
ACR70
ACR50
ACR70
Burmester GR. Presented at ACR 2011; Presentation #L7.
119
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 GMCSFRα may be a novel approach in the treatment of
RA and supports future clinical studies
Burmester GR. Presented at ACR 2011; Presentation #L7.
120
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-tosevere 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
ACR20
ACR50
ACR70
% achieving ACR responses
80
70
60
50
40
30
20
10
0
Placebo
100 mg
q2w
150 mg 100 mg qw 200 mg 150 mg qw
q2w
q2w
Sarilumab dose
Genovese MC, et al. Presented at ACR 2011; Presentation #L2.
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, placebocontrolled, 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
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
ACR20 at Week 12
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
% achieving
sUA < 6mg/dL at week 12
60%
49%†
50%
45%*
39%*
40%
33%
30%
20%
18%
10%
0%
Placebo
5 mg
10 mg
20 mg
BCX4208 dose
*p<0.05; †p<0.001
Becker LM. Presented at ACR 2011; Presentation #L10.
40 mg
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 1to-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
• 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
*p < 0.05 vs FREEDOM baseline; †p < 0.0001 vs FREEDOM and extension baseline.
Brown JP. Presented at ACR 2011; Presentation #L8.
Spondylarthropathies:
Recent Insights
Highlights of an ACR Clinical
Symposium,
Tuesday, November 8
Summarized by Dr. Majed Khraishi
131
List of Presentations in this Section
Speaker / primary
author
Title
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
Clinical Symposium:
Spondylarthropathies: Recent Insights. ACR 2011; Tues., Nov. 8.
Abstract #
132
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
• 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
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.
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. Clinical Symposium " Spondylarthropathies: Recent Insights".
Presented at ACR 2011.
Evidence for Methotrexate in PsA:
MTX in Psoriatic Arthritis (MIPA) Trial
Placebo
% of patients
% of patients
MTX
3 months
Kingsley GH. Clinical Symposium " Spondylarthropathies: Recent Insights".
Presented at ACR 2011.
6 months
Evidence for Methotrexate in PsA:
MTX in Psoriatic Arthritis (MIPA) Trial
MTX
Placebo
Kingsley GH. Clinical Symposium " Spondylarthropathies: Recent Insights".
Presented at ACR 2011.
Evidence for Methotrexate in PsA:
Conclusions from the MIPA Trial
• MTX In PsA:
 Improves symptoms
 Has no effect on joint counts or acute phase
response
 Is a “symptom modifying agent” and not a
“DMARD”
Kingsley GH. Clinical Symposium " Spondylarthropathies: Recent Insights".
Presented at ACR 2011.
Radiographic Changes in Patients
with Early Psoriatic Arthritis
• Key Findings:
 Radiological damage was detected in 32% of
patients with Early PsA and was associated
with increased CRP
 76% of those with damaged acquired it within
the 1st year of symptom onset
 The increased incidence of axial and DIP joint
involvement are in agreement with previous
studies showing that they represent the most
common sites in PsA
 Asymmetric oligoarthritis was not a dominant
pattern in this cohort
Khraishi M, et al. Presented at ACR 2011; Poster #1548.
140
Impact of Body Weight in
Rheumatic Disease
Selected Highlights from Various
ACR Sessions
Summarized by Dr. Robert Offer
141
List of Presentations in this Section
Speaker /
primary author
Title
Smolen JS
Impact of Body Mass Index on Response to
Etanercept Therapy in Subjects with Moderately
Active Rheumatoid Arthritis in the PRESERVE Trial
410
Heimans L
Body Mass Index Is Associated with Decreased
Response to Initial and Delayed Treatment with
Dose Escalated Infliximab in Patients with Recent
Onset Rheumatoid Arthritis
416
Ottaviani S
Body Mass Index Influences the Response to
Infliximab in Ankylosing Spondylitis
530
Various ACR sessions. ACR 2011; Nov. 6-8.
Abstract #
142
List of Presentations in this Section
Speaker /
Primary author
Title
Wolfe F
The Effect of Body Mass Index On the
Outcomes of Rheumatoid Arthritis
2586
Greenberg JD
Effect of Weight, Body Mass Index and
Weight-Based Dosing on Persistency
of Anti-TNFs in Psoriatic Arthritis
1310
Katz PP
Identifying Obesity in Rheumatoid
Arthritis: Current BMI Definition of
Obesity Does Not Accurately Reflect
Body Composition
799
Various ACR sessions. ACR 2011; Nov. 6-8.
Abstract #
143
Does BMI Affect Outcomes
With Biologics in RA?
Probability
of DAS28
Remission*
Response
to ETN-MTX
by BMI category
at Week 36 in Subjects w/ Moderate RA
% of subjects
Variable
BMI
BMI 25 BMI
<25 kg/m2 <30 kg/m2 ≥30 kg/m2
p
value
Remission (<2.6)
70.8
68.1
56.7
0.01
LDAS (<3.2)
87.5
86.5
79.5
0.05
Remission (≤2.8)
29.5
28.0
17.3
0.02
LDA (<10)
85.4
81.2
78.7
0.06
Remission (≤3.3)
27.7
26.7
16.0
0.02
LDA (<11)
86.8
83.8
81.6
0.13
DAS28
CDAI
SDAI
Smolen JS, et al. Presented at ACR 2011; Poster #410.
Is Being Overweight / Obese a Predictor of Poor
Response to Infliximab? (BeSt Sub-analysis)
• Patients with high BMI
have lower chance of
responding to
infliximab, even if the
infliximab is increased
up to 10 mg/kg
• Other predictors of
poor response were
female sex and high
DAS
Heimans L, et al. Presented at ACR 2011; Poster #416.
BMI
Proportion
Achieving
DAS≤2.4
x 6 months
<25
84%
25-30
68%
>30
64%
Does BMI Affect Outcomes in SpA Patients
Treated with Biologics?
• Subjects:
 155 patients with active AS, treated with
infliximab 5 mg/kg (retrospectively identified)
• Outcomes:
 50% improvements in BASDAI, VAS pain,
CRP, and total NSAID dose
• Results:
 Outcomes with infliximab were significantly
better at 6 months for all measures with BMI ≤
30 kg/m2 compared to BMI >30 kg/m2 (p values
0.0001 to 0.0275)
Ottaviani S, et al. Presented at ACR 2011; Poster #530.
The Effect of Body Mass Index on Mortality
and Clinical Status in Rheumatoid Arthritis
• Objectives:
 To determine the % of RA patients who are
underweight, normal weight, overweight and
obese
 To define the relationship of BMI groups with
CVD & all-cause mortality
 To quantify the effect of BMI status on
comorbidity, symptoms, treatment and direct
medical costs
Wolfe F. Presented at ACR 2011; Presentation #2586.
The Effect of Body Mass Index on Mortality
and Clinical Status in Rheumatoid Arthritis
• Methods:
 24,535 RA patients over 12.3 years
 Divided patients into 3 age groups, <50, 50-70,
and >70 years
– Cox regression models within each age
stratum
 BMI categories (kg/m2)
– <18.5 (underweight)
– 18.5 to <25 (normal weight, reference category)
– 25 to <30 (overweight)
– ≥30 (obese)
Wolfe F. Presented at ACR 2011; Presentation #2586.
Adjusted All-cause Mortality in RA
by Body Mass Index
Age
group
(yrs)
RR (95% CI) vs. Normal Weight (BMI 18.5 - <25 kg/m2)
Underweight
(BMI <18.5 kg/m2)
Overweight
(BMI 25 - <30 kg/m2)
Obese
(BMI ≥ 30 kg/m2)
<50
1.3 (0.6 – 3.1)
0.7 (0.5 – 1.1)
1.0 (0.7 – 1.5)
50-70
2.1 (1.6 – 2.8)*
0.9 (0.8 – 1.0)*
0.9 (0.8 – 1.0)*
>70
1.5 (1.2 – 1.8)*
0.8 (0.7 – 0.9)*
0.8 (0.7 – 0.9)*
All
1.9 (1.6 – 2.2)*
0.8 (0.7 – 0.8)*
0.6 (0.5 – 0.6)*
The paradoxical protective effect of obesity over age 50 is
unexplained as every 5 unit increase in BMI was associated with
26% higher incidence of diabetes and 35% higher incidence of
hypertension.
*Statistically significant vs. normal weight
Wolfe F. Presented at ACR 2011; Presentation #2586.
Predictors of Efficacy of
TNF-inhibitors in Psoriatic Arthritis
Hazard Ratio
95% CI
Fixed dosing (vs. weightbased) anti-TNF
1.38
0.90, 2.11
0.140
BMI (≥30) vs BMI <30
1.52
1.08, 2.14
0.017
Pt. Pain (≥4 vs <4)
1.48
1.05, 2.10
0.026
Female vs Male
1.64
1.17, 2.29
0.004
Disabled
1.78
1.00, 3.16
0.050
History of CVD
2.68
1.31, 5.49
0.007
Duration of PsA
0.98
0.96, 1.00
0.06
Greenberg JD. Presented at ACR 2011; Poster #1310.
p-value
Need for New Definition of Obesity in RA
• N=141 from a long term RA cohort
• Compared body composition measured by
DEXA (% body fat) to BMI (>30 kg/m2)
Total group:
% obese
Men:
% obese
Women:
% obese
DEXA
58%
80%
44%
BMI
27%
29%
26%
• RA patients have less muscle and more fat than
predicted by BMI
• This study found best BMI definition for obesity
in RA is > 24.7 for men and > 25.7 for women
Katz PP. Presented at ACR 2011; Presentation #799.
Impact of Environmental Health
on Autoimmunity
Highlights of an ACR Clinical
Symposium,
Sunday, November 6
Summarized by Dr. Hector Arbillaga
152
List of Presentations in this Section
Speaker
Title
Miller F
The Environment and Autoimmune Diseases – Where we
stand in 2011
James JA
The Role of Gene X Environment Interactions in
Autoimmunity
Cooper GS
Smoking and Silica Exposure-Models for Exploring
Environmental Triggers of Disease
Clinical Symposium:
Impact of Environmental Health on Autoimmunity. ACR 2011; Sun., Nov. 6.
153
Chemical Factors Associated with
Autoimmune Diseases
• Crystalline silica exposure contributes to
development of RA, SScl, SLE and antineutrophil cytoplasmic antibody (ANCA)-related
diseases including vasculitis and
glomerulonephritis
• Solvent exposure contributes to development
of SScl
• Smoking contributes to the development of
anticitrullinated protein/peptide antibody
(ACPA)-positive and anti-rheumatoid factor
(RF)-positive RA, and there is an interaction
with the HLA shared epitope
Miller F. Clinical Symposium "Impact of Environmental Health on Autoimmunity".
Presented at ACR 2011.
Physical Factor Associated with
Autoimmune Diseases
• An inverse association exists between
increased ultraviolet radiation exposure and the
decreased risk of development of MS
Miller F. Clinical Symposium "Impact of Environmental Health on Autoimmunity".
Presented at ACR 2011.
Biological factors Associated with
Autoimmune Diseases
• Gluten contributes to the development of GSE
• Dietary intake of certain lots of L-tryptophan
contribute to the development of eosinophilia
myalgia syndrome
• Dietary intake of 1,2-di-oleyl ester (DEPAP) and
oleic anilide-contaminated rapeseed oil
contributes to the development of toxic oil
syndrome
Miller F. Clinical Symposium "Impact of Environmental Health on Autoimmunity".
Presented at ACR 2011.
Expert Panel Conclusions on Environment
Factors for Autoimmune Diseases
• Epidemiology and other approaches have and will continue
to contribute to our knowledge of environmental risk
factors for AID
• More cost-effective, validated methods for assessing
human exposures are needed
• More research into phenotypes, genotypes, synergies of
multiple exposures and mechanisms are needed
• Understanding the effects of the timing of exposures (life
course, latencies) and dose-response effects are critical
• Increased resources in this area are justified as knowledge
of the risks conferred by environmental factors in specific
genetic contexts could pave the way for prevention of
certain AIDs in the future
Miller F. Clinical Symposium "Impact of Environmental Health on Autoimmunity".
Presented at ACR 2011.
The Role of Gene X Environment
Interactions in Autoimmunity: Summary
• Current data support a temporal association of EBV
seroconversion with onset of lupus autoantibodies
• Lupus patients mount a different humoral immune
response to EBNA-1 compared to normal controls
• 24% of FDRs make anti-PPPGRRP compared to <3%
of controls (p<10-11); Anti-PPPGMRPP correlates
with anti-PPPGRRP and anti-PPPGMRPP correlated
with anti-Sm
• SLE patients with select IRF5 haplotypes show
differential expression of B cell, interferon and TLR
associated genes compared to low-risk haplotype
patients
James JA. Clinical Symposium "Impact of Environmental Health on Autoimmunity".
Presented at ACR 2011.
158
The Role of Gene X Environment
Interactions in Autoimmunity: Summary, cont'd
• Multiple-sclerosis-associated HLA associations
show differential interactions with herpes viral
exposures and vitamin D deficiency in pediatric
MS
• IRF5 has a number of Vitamin-D responsive
elements
• Extensive work remains to more fully
understand environment and genetic
interactions in autoimmune disease etiology
and pathogenesis
James JA. Clinical Symposium "Impact of Environmental Health on Autoimmunity".
Presented at ACR 2011.
159
Smoking and Rheumatoid Arthritis:
Influence on Pathogenesis
Smoking
Generation of modified peptides
(citrullination) in lungs
Activation of adaptive immune response
- Antigen presentation (DRB1-SE binding)
- T-cell activation (PTPN22)
"Priming" for systemic immunity
Cooper GS. Clinical Symposium "Impact of Environmental Health on Autoimmunity".
Presented at ACR 2011.
160
Silica Dust and Autoimmune Disease
• NOT Limited to a single disease
 RA, scleroderma, SLE, systemic vasculitis
 Breadth of the research underappreciated by our (narrow)
individual research perspectives
• NOT limited to very high exposures / silicosis patients
 Relevant for disease seen in community settings (not just
occupational cohorts of miners)
 Relevant for women (but may need different/better exposure
assessments for women)
• Short-term, high intensity exposures may be relevant
 Does an OSHA 8-hour TWA PEL provide adequate
protection for autoimmune rheumatic diseases?
Cooper GS. Clinical Symposium "Impact of Environmental Health on Autoimmunity".
Presented at ACR 2011.
161
Orthopedics, Low Back Pain, and
Rehabilitation
Highlights of an ACR Poster
Session, Monday, November 7
Summarized by Dr. Anthony Russell
162
List of Presentations in this Session
Abstract #
Primary author
Title
Micca JL
The Efficacy and Safety of Duloxetine
Treatment in Older Patients with
Osteoarthritis Knee Pain: A Post Hoc,
Subgroup Analysis of Data From 2
Placebo-Controlled Trials
1094
Fidelholtz J
A Phase 3 Placebo- and OxycodoneControlled Study of Tanezumab in
Adults with Osteoarthritis
1095
Feist E
Efficacy and Safety of Tanezumab
Added on to Diclofenac in Patients
with Knee or Hip Osteoarthritis
(NCT00864097)
1096
Poster session:
Orthopedics, Low Back Pain, and Rehabilitation. ACR 2011; Mon., Nov. 7.
163
Duloxetine for Osteoarthritis in
Older Adults: Pooled Subgroup Analysis
• Objective: To examine the efficacy and safety of duloxetine
(DLX) treatment in older aged patients with OA knee pain
• Methods: Post-hoc analysis of two 3-month RCTs in patients
with symptomatic knee OA
 Patients were randomized to DLX 60mg QD vs. placebo for 7
weeks
 For the remaining 6 weeks:
– Study I: DLX patients were re-randomized to receive
either DLX 60 mg QD or 120 mg QD
– Study II, only DLX non-responders had their dose
increased to 120 mg
 Pain severity (0-10) was assessed daily and recorded in
patient diaries
 Treatment-emergent adverse events were evaluated
Micca JL, et al. Presented at ACR 2011; Poster #1094.
164
Duloxetine for Osteoarthritis in
Older Adults: Changes in Daily Pain Diaries
(< 65 years)
*p < 0.05; †p < 0.01; ‡p < 0.001
Micca JL, et al. Presented at ACR 2011; Poster #1094.
(≥ 65 years)
165
Phase 3 Study of Tanezumab
for Adults with Osteoarthritis
• Objective: To investigate the efficacy & safety of
tanezumab (TNZ) vs. oxycodone continuous release (OXY)
as analgesic treatment for knee or hip OA
• Methods: Double-blind, placebo-controlled, 16-week study
 Patients received up to two doses of TNZ (10 or 5 mg IV
in 8-week intervals), OXY (10-40 mg every 12 hours; uptitrated & modified according to tolerability & pain relief
or placebo after prior analgesic pain medication washout
 Primary endpoint: WOMAC Pain subscale score
• Early trial completion: Study was only partially completed
due to a FDA-imposed clinical hold so primary endpoint
timing was amended from Week 16 to Week 8 to maximize
planned analyses
Fidelholtz J, et al. Presented at ACR 2011; Poster #1095.
166
Phase 3 Study of Tanezumab for Adults
with Osteoarthritis: Week 8 Results
Fidelholtz J, et al. Presented at ACR 2011; Poster #1095.
167
Tanezumab Added to Diclofenac
for Hip or Knee OA
• Objective: To evaluate efficacy and safety of i.v.
tanezumab (TZB) added to oral diclofenac sustained
release (DSR) in patients with hip or knee OA
• Methods: Randomized, double-blind, placebocontrolled study
 Patients (N=604) with moderate to severe knee or
hip OA tolerating stable oral diclofenac 150
mg/day were randomized to i.v. TZB 2.5, 5, or 10
mg, or placebo at weeks 0, 8, and 16
 Co-primary efficacy endpoints: WOMAC Pain
subscale, WOMAC Physical Function subscale,
and Patient Global Assessment of OA at week 16
Feist E, et al. Presented at ACR 2011; Poster #1096.
168
Tanezumab Added to Diclofenac
for Hip or Knee OA
PBO: Placebo; DSR: Diclofenac sustained release; TZB: tanezumab
Feist E, et al. Presented at ACR 2011; Poster #1096.
Osteoporosis and Metabolic
Bone Disease: Clinical Aspects
and Pathogenesis
Highlights of an ACR Concurrent
Abstract Session,
Monday, November 7
Summarized by Dr. Philip Baer
170
List of Presentations in this Section
Speaker
Title
Amin S
Fracture Risk Is Increased in Young
Women with Rheumatoid Arthritis
1632
Does Identification of Prevalent
Vertebral Fracture on Densitometric
Vertebral Fracture Assessment (VFA)
in Clinical Practice Influence Physician
Prescribing Behavior?
1634
Schoushoe JT
Concurrent abstract session: Osteoporosis and Metabolic Bone Disease:
Clinical Aspects and Pathogenesis. ACR 2011; Mon., Nov. 7.
Abstract #
171
Fracture Risk By Age and Sex in RA
Hazard ratio (95% CI)
All
< 50 years
≥ 50 years
OP Fx
1.7 (1.4 – 2.2)
4.3 (2.4 – 7.8)
1.4 (1.1 – 1.8)
Any Fx
1.6 (1.3 – 1.9)
2.4 (1.6 – 3.5)
1.4 (1.1 – 1.7)
OP Fx
1.6 (1.1 – 2.4)
1.4 (0.7 – 3.0)
1.8 (1.1 – 2.8)
Any Fx
1.4 (1.02 – 1.9)
1.7 (0.9 – 3.2)
1.4 (0.9 – 2.0)
Women
Men
*excludes any severe trauma fracture
Amin S. Presented at ACR 2011; Presentation #1632.
Fracture Risk in RA: All Women
Amin S. Presented at ACR 2011; Presentation #1632.
Fracture Risk in RA: Women With Baseline
Age < 50 Years
Amin S. Presented at ACR 2011; Presentation #1632.
Fracture Risk in RA: Women < 50 Years &
Follow-up Limited to Age 50 Years
Amin S. Presented at ACR 2011; Presentation #1632.
Fracture Risk in RA: All Men
Amin S. Presented at ACR 2011; Presentation #1632.
Fracture Risk in RA: Men With
Baseline Age < 50 Years
Amin S. Presented at ACR 2011; Presentation #1632.
Fracture Risk By Age and Sex in RA:
Conclusions
• Men >50 yrs with RA appear to be at increased
risk for future fracture, but few fractures
occurred before age 50 years
• Women <50 yrs with RA are not only at high risk
for future fracture, but their fracture risk is
increased even before they reach age 50 years
• Fracture-prevention strategies for young
women with RA are thus important to consider
Amin S. Presented at ACR 2011; Presentation #1632.
Influence of Identified Vertebral Fractures
on Prescribing Behavior
• Objective:
 To determine whether the performance of a
vertebral fracture assessment (VFA)
influences provider prescribing behavior?
• Methods:
 Merging of Electronic Health Record and
Bone Densitometry Data (n=45,889)
 Association of Performance of VFA with use
of fracture prevention medication
 Data collection ongoing
Schoushoe JT. Presented at ACR 2011; Presentation #1634.
Standing Orders for VFA At This Center
• Low Bone Density (T-score of lumbar spine,
total hip, or femoral neck ≤ -1.5) PLUS one of
the following
 Age ≥ 65 years
 Height loss ≥ 1.5 inches (4 cm)
 On systemic glucocorticoid (cortisone-like)
medications
• Those who meet criteria: pre-test probability for
1 or more prevalent vertebral fractures > 10%
Schoushoe JT. Presented at ACR 2011; Presentation #1634.
Association of VFA Positive Results with Use
or Start of Fracture Prevention Medication After DXA
Population
Odds Ratio (95% CI)
Osteopenia (n=298)
2.41
(1.30– 4.46)
Osteopenia NOT on medication on
DXA date (n=197)
4.26
(1.89 – 9.62)
Schoushoe JT. Presented at ACR 2011; Presentation #1634.
Do VFA-positive Patients Receive
Appropriate Follow-up?
• Definition of appropriate Follow-up to Positive VFA:
 Medication started or
 Reasons for NOT being on medication
documented
• Within 299 nested case-control cohort:
 42 with a positive VFA with appropriate follow-up
 4.7% of those who were NOT on medication after
DXA/VFA had a positive VFA and inappropriate
follow-up
• Within entire sample: 4328*0.047 = 204
 Proportion with a positive VFA who are followed
up appropriately: 42/246 = 17.1%
Schoushoe JT. Presented at ACR 2011; Presentation #1634.
Influence of Identified Vertebral Fractures
on Prescribing Behavior: Conclusions
• VFA performance at the time of DXA influences
use of fracture prevention medication
• Positive VFA results associated with start of
medication especially among those not on
medication on DXA/VFA date
• A significant proportion of those with a
possible or definite vertebral fracture on VFA
may not be receiving appropriate follow-up
Schoushoe JT. Presented at ACR 2011; Presentation #1634.
Systemic Sclerosis (SSc),
Fibrosing Syndromes and
Raynaud's—Clinical Aspects
and Therapeutics
Highlights of ACR Concurrent
Abstract and Poster Sessions,
Monday, November 7
Summarized by Drs. Clode Lessard
& Janet Pope
184
List of Presentations in this Section
Speaker
Title
Johnson SR
Effect of Warfarin On Survival In SclerodermaAssociated and Idiopathic Pulmonary Arterial
Hypertension. A Bayesian Approach to Evaluating
Treatment In Uncommon Disease
2481
Schreiber BE
Diffusion of Carbon Monoxide Predicts Survival in
Systemic Sclerosis Patients with Pulmonary
Hypertension and Interstitial Lung Disease
2482
Seibold JR
Digital Ischemic Ulcers in Scleroderma Treated with
Oral Treprostinil Diethanolamine: A Randomized,
Double-Blind, Placebo-Controlled, Multicenter Study
2483
RodriguezReyna TS
Microvascular Damage and Cardiac Fibrosis Detected
by Heart MRI are a Hallmark of Systemic
Sclerosis Heart Involvement
2484
Concurrent abstract and poster sessions: Systemic Sclerosis (SSc), Fibrosing
Syndromes and Raynaud's—Clinical Aspects and Therapeutics. ACR 2011; Mon., Nov. 7.
Abstract #
185
List of Presentations in this Section, cont'd
Speaker /
Primary author
Title
Domsic RT
Development and Internal Validation of a Two-Year
Mortality Risk Prediction Rule in Early Diffuse
Systemic Sclerosis Patients
2485
Gelber AC
Race and Mortality Risk in Scleroderma
2486
Chakravarty EF
A Pilot Study of Abatacept for the Treatment of
Patients with Diffuse Cutaneous Systemic Sclerosis
707
Meunier M
Outcomes of Systemic Sclerosis Associated
Polyarthritis Patients Treated by Biotherapies
Tocilizumab or Abatacept: A EUSTAR Observational
Study
1462
Concurrent abstract and poster sessions: Systemic Sclerosis (SSc), Fibrosing
Syndromes and Raynaud's—Clinical Aspects and Therapeutics. ACR 2011; Mon., Nov. 7.
Abstract #
186
List of Presentations in this Section, cont'd
Speaker
Title
Jordan S
Effects and Safety of Rituximab in Systemic Sclerosis:
An Analysis From the European Scleroderma Trial and
Research Group
702
Chung L
Effect of the ETA Selective Endothelin Receptor
Antagonist Ambrisentan on Digital Ulcers in Patients
with Systemic Sclerosis: Results of a Prospective Pilot
Study
668
Concurrent abstract and poster sessions: Systemic Sclerosis (SSc), Fibrosing
Syndromes and Raynaud's—Clinical Aspects and Therapeutics. ACR 2011; Mon., Nov. 7.
Abstract #
187
Should Scleroderma With Pulmonary Arterial
Hypertension Be Treated with Warfarin?
• Objective: To determine if warfarin use could
increase survival by 6 months
• Subjects: 275 patients identified by chart review
from Toronto Scleroderma and Pulmonary
Hypertension Programs
• Conclusion: Warfarin did not significantly
increase survival
• Limitations: Low incidence of disease / warfarin
use erratic / INR unknown / complicated and
hypothetic statistical analysis
Johnson S. Presented at ACR 2011; Presentation #2483.
Predictors of Survival in Scleroderma With
Pulmonary Hypertension
Predictors from univariate analysis
p value
Functional class
0.007
DLCO % predicted
0.03
FVC/DLCO
0.006
KCO % predicted
< 0.0005
Predictors from Multivariate Cox Analysis
p value
KCO % predicted
Schreiber BE. Presented at ACR 2011; Presentation #2484.
0.017
Is Treprostinil Effective at Healing Ischemic
Digital Ulcers in Scleroderma Patients?
• Objective: To assess the effect of oral
treprostinil in reducing “Net Ulcer Burden” in
patients with systemic sclerosis (SSc) at 20
weeks
• Design: RCT comparing oral treprostinil (serum
levels were measured) to placebo
 Qualifying Digital Ulcers
– Vascular in origin
– Without bone infection or calcinosis
– Distal to the proximal interphalangeal joint
– Volar to the median of the finger (palm
side)
Seibold J. Presented at ACR 2011; Presentation #2483.
Is Treprostinil Effective at Healing Ischemic
Digital Ulcers in Scleroderma Patients?
• Results: Overall negative study, but with some
positive results
 No significant improvement in ulcer healing at
20 weeks compared to placebo
 No effect on time to healing of ulcers
 Good healing of ulcers in placebo group
 Medication more effective in ACA-negative
patients
 Improvement in function, grip strength,
patient impression of overall change and
Raynaud and physician VAS
Seibold J. Presented at ACR 2011; Presentation #2483.
What Proportion of Scleroderma Patients
Have Cardiac Fibrosis?
• Mexican study of 62 scleroderma patients (47% diffuse/ 53%
limited) without cardiovascular risk factors or history
• Results:

ON MRI, 58.6% of diffuse patients had cardiac involvement
compared to 33% in limited form
Prevalence of cardiac fibrosis
Late enhancement on MRI



Total
Diffuse
Limited
p
28 (45%)
17 (58.6%)
11 (33.3%)
0.04
6.7% of the heart had fibrosis in diffuse Scl pts compared to
1.6% in limited patients
LVEF was 66% in absence of fibrosis compared to 56% with
fibrosis
Basal area more involved than middle and apex
Rodriguez-Rayna TS. Presented at ACR 2011; Presentation #2484.
What Are the Mortality Predictors in Early
Diffuse Scleroderma?
• Design: Retrospective analysis of more than 150
variables
• Subjects: 387 patients with < 2 years of evolution of
diffuse scleroderma
 Mean age: 50 years, 75% women
• Results: 2-year mortality rate: 20%
Variables predicting mortality
Age at first visit
Rapid progression of skin
involvement
Severity of GI involvement
Domsic RT. Presented at ACR 2011; Presentation #2485.
Severity of muscle involvement
Severity of cardiac involvement
Anemia
Is Race Related to Mortality Risk in
Scleroderma?
Relative
• Design: Chart review from
1990Risk,
to 2009 of
Model
Black compared to
95%CI
scleroderma patients seen
at
the
scleroderma
White Patients
clinic in Baltimore (n=2217)
Unadjusted
1.3
1.1 – 1.5
Age, duration-adjusted
1.6
1.3 – 1.9
Age, duration, gender, subtypeadjusted
1.4
1.2 – 1.7
Age, duration, gender, subtype,
Scl-70-adjusted
1.6
1.2 – 2.1
Age, duration, gender, subtype,
centromere-adjusted
1.5
1.1 – 1.9
Gelber AC. Presented at ACR 2011; Presentation #2486.
Abatacept for Diffuse Cutaneous Systemic
Sclerosis: Pilot Study
Abatacept
(n=7)
Placebo
(n=3)
p value
-0.04 (0.2)
0.25
0.56
Absolute change in mRSS
-8.6 (7.5)
-2.3 (15.0)
0.059
% change in mRSS
-33 (29.0)
-6.2 (52.3)
0.31
-11.9 (18.1)
-17.3 (23.2)
0.048
-8 (7.6)
-2.7 (6.7)
0.023
Change in Patient Pain
-11.4 (8.3)
-15.0 (25.1)
0.18
Change in FVC
1.3 (8.5)
0.3 (8.5)
0.72
Change in DLCO
2.0 (6.3)
- 7.4 (10.7)
0.84
# Adverse events
7
7
NA
Change in HAQ-DI
Change in Physician Global
Change in Patient Global
Chakravarty EF, et al. Presented at ACR 2011; Poster #707.
Systemic-Sclerosis-Associated Polyarthritis Treated with
Tocilizumab or Abatacept: EUSTAR Observational Study
• Design: Observational study of 13 patients with
SSc with arthritis
 Mean age 50, 10 years disease, 1/2 diffuse
(dcSSc), 1/3 CCP+
• Results:
 Tocilizumab 8 mg/kg/month (n=9): DAS went
from 5.0 to 2.2
 Abatacept 10 mg/kg/month (n=4): DAS went
from 4.4 to 1.8
 No changes in mRSS or HAQ
Meunier M, et al. Presented at ACR 2011; Poster #1462.
Effects and Safety of Rituximab
in Systemic Sclerosis (EUSTAR)
•
Design: Retrospective EUSTAR cohort
•
Subjects: 72 SSc patients
•

52 dcSSc / 19 lcSSc

Mean 6 years disease duration (3-10 yrs)

Treated with 2 X 1000 mg rituximab 2 weeks apart

28 / 72 were on other DMARDs (50% MTX)
Results:

MRSS (N=47) went from 18.2 to 14.6 (p<0.0002)
– Among dcSSc with high skin scores (N=26), MRSS went from
26.6 to 21 (p<0.0001)

Activity score improved

No effect on PFTs, HRCT

Among those with arthritis (n-=8), DAS decreased from 4.8 to 3.7

Among those with myositis, CK decreased
Jordan S, et al. Presented at ACR 2011; Poster #702.
Ambrisentan for Digital Ulcers in Patients
with Systemic Sclerosis: Pilot Study
Mean # of Total DU per Patient
NB: Not an RCT, no control group.
Chung L, et al. Presented at ACR 2011; Poster #668.
Complicated Raynaud's
Phenomenon
Highlights of an ACR Clinical
Symposium, Sunday, November 6
Summarized by Dr. Philip Baer
199
List of Presentations in this Section
Speaker
Title
Wigley F
Complicated Raynaud’s Phenomenon
Clinical Symposium
Complicated Raynaud's Phenomenon. ACR 2011; Sun., Nov. 6.
200
What is needed to make a Diagnosis of
Raynaud’s Phenomenon?
• Ask the following questions:
1.
Are your fingers unusually sensitive to cold?
2.
Do your fingers change color when they are
exposed to cold?
3.
Do they turn white, blue or both?
• Confirmed if positive response to all three
questions
• Excluded if response to 2 and 3 are negative
Wigley F. Clinical Symposium "Complicated Raynaud’s Phenomenon".
Presented at ACR 2011.
Thermoregulatory Vessels
Wigley F. Clinical Symposium "Complicated Raynaud’s Phenomenon".
Presented at ACR 2011.
Primary Raynaud’s Phenomenon
Involves All Digits Symmetrically
Wigley F. Clinical Symposium "Complicated Raynaud’s Phenomenon".
Presented at ACR 2011.
In Raynaud's, the Thumb is Less Often
Involved But Not Spared
Wigley F. Clinical Symposium "Complicated Raynaud’s Phenomenon".
Presented at ACR 2011.
In Raynaud's, Pallor Beyond the MCP Joints
is Worrisome
Wigley F. Clinical Symposium "Complicated Raynaud’s Phenomenon".
Presented at ACR 2011.
Treatment Considerations for Raynaud's
Wigley F. Clinical Symposium "Complicated Raynaud’s Phenomenon".
Presented at ACR 2011.
Treatment Considerations for Raynaud's,
Cont'd
Wigley F. Clinical Symposium "Complicated Raynaud’s Phenomenon".
Presented at ACR 2011.
Treatment Considerations for Raynaud's:
Prostacyclin Analogs
• The Cochrane review of 7 clinical trials using
prostacyclin analogs in RP secondary to
scleroderma found similar results, with the
analysis favoring drug with respect to attack
frequency and severity, physician assessment
of treatment, and improvement in digital lesions
Pope J, et al. The Cochrane Library 2009.
Cited by Wigley F. Clinical Symposium "Complicated Raynaud’s Phenomenon".
Presented at ACR 2011.
Treatment Algorithm for Vascular Disease
Wigley F. Clinical Symposium "Complicated Raynaud’s Phenomenon".
Presented at ACR 2011.
Vasculitis
Highlights of ACR Poster
Sessions, November 7 & 8
Summarized by Drs. Robert Offer and Peter
Panopalis
210
List of Presentations in this Section
Primary author
Title
Schmidt J
Statin Exposure and Risk of Giant Cell
Arteritis: A Case Control Study
1512
Mariette X
Results of a Randomized Controlled
Study of Adalimumab for Steroid
Sparing in Patients with Giant-Cell
Arteritis
1508
Catanoso MG
Tocilizumab: A Novel Therapy for
Patients with Large-Vessel Vasculitis
1505
Unizony S
Tocilizumab for the Treatment of Large
Vessel Vasculitis (Giant Cell Arteritis,
Takayasu Arteritis) and Polymyalgia
Rheumatica: A Case Series
1507
Poster sessions. Vasculitis. ACR 2011; Nov. 7 & 8.
Abstract #
211
List of Presentations in this Section
Primary Author
Title
Pagnoux C
Are Patients with ANCA-Associated
Vasculitis Entered In Clinical Trials
Representative of Patients Followed In
Observational Cohorts?
2368
Tomasson G
Optimal Definition for the Duration of
Sustained Remission in ANCAAssociated Vasculitis
2369
Davids ML
Mental Health As a Predictor of
Disease Flare in Granulomatosis with
Polyangiitis (Wegener's
Granulomatosis)
2371
Poster sessions. Vasculitis. ACR 2011; Nov. 7 & 8.
Abstract #
212
Effect of Statin Use on
Risk of Giant Cell Arteritis
• Objective: To examine a potential association
between statin exposure and the risk of
developing GCA
• Method: Retrospective case-control study
 Review of medical records of all patients with
biopsy-proven GCA (n=297)
 Randomly selected population-based controls
matched for sex, age, and calendar year
 Investigators analyzed the association
between statin exposure and the risk of GCA,
with adjustment for cardiovascular risk
factors
Schmidt J, et al. Presented at ACR 2011; Poster #1512.
% with statin use at baseline
Statins Reduce the Risk of Giant Cell
Arteritis
• Patients with GCA
were less often users
of statins compared to
controls
100%
80%
60%
40%
20%
33.3%
14.1%
0%
GCA
Controls
Schmidt J, et al. Presented at ACR 2011; Poster #1512.
• After adjustments for
CV risk factors, statin
use was associated
with a lower risk of
GCA
•
OR: 0.31 (95% CI 0.15 to
0.6, p = 0.0006)
Mean change in prednisone dose
No Steroid-sparing Effect for
Adalimumab in Giant Cell Arteritis
Mariette X, et al. Presented at ACR 2011; Poster #1508.
ACR 2011
Tocilizumab for Large Vessel Vasculitis:
Case Series
• Subjects: 6 patients with large vessel vasculitis
 1 giant cell arteritis, 4 Takayasu arteritis and 1
thoracic aortitis w/ retroperitoneal fibrosis
 2 treatment-naïve, 4 failed immunosuppressants
ESR (mm/h)
CRP (mg/dL)
ITAS
KERR
Before
TCZ
After
TCZ
Before
TCZ
After
TCZ
Before
TCZ
After
TCZ
Before
TCZ
After
TCZ
PT 1
45
3
4.02
0.06
4
0
4
0
PT 2
67
2
0.99
0.05
3
0
4
0
PT 3
84
2
4.80
0.01
8
0
4
1
PT 4
95
4
5.42
0.07
3
0
4
2
PT 5
33
6
4.27
0.12
3
0
3
1
PT 6
69
12
0.88
0.04
2
0
4
0
Catanoso MG, et al. Presented at ACR 2011; Poster #1505.
Tocilizumab for Large Vessel Vasculitis:
Case Series
• Subjects: 7 patients with large vessel
vasculitis
 2 giant cell arteritis, 4 Takayasu arteritis
and 1 polymyalgia rheumatica
 6 subjects had failed at least one DMARD
or infliximab in addition to prednisone
• Results:
 Within 8 weeks, all subjects tapered
prednisone dose to a mean of < 5 mg
 All patients have entered and maintained
remission
Unizony S, et al. Presented at ACR 2011; Poster #1507.
ACR 2011
Statistically Significant Differences Between Patients with ANCAAssociated Vasculitis in Observational Cohorts & Clinical Trials
Observational
Cohorts (n=423)
Clinical Trials
(n=220)
P value
Microscopic polyangiitis, n (%)
26 (6.1)
41 (18.6)
<0.001
Age at diagnosis, years (± SD)
46.5 ± 17.3
56.6 ± 13.9
<0.001
Lung involvement, n (%)
275 (65.6)
169 (78.2)
<0.001
CV involvement, n (%)
25 (6.0)
37 (17.5)
<0.001
GI manifestations, n (%)
28 (6.7)
26 (12.3)
0.02
Renal involvement, n (%)
231 (53.7)
174 (80.9)
<0.001
131.4 ± 142
196.0 ± 218
<0.001
Anti-MPO positive
58 (15.3)
51 (23.2)
0.01
BVAS
16.7 ± 7.5
22.4 ± 7.5
<0.001
Mean follow-up since
diagnosis, months (± SD)
72.5 ± 61.7
61.6 ± 44.3
0.02
14 (3.3)
49 (22.3)
<0.001
256 (60.5)
101 (45.9)
0.01
Variable
Mean creatinine (µmol/l ± SD)
Death
Relapse
Pagnoux C, et al. Presented at ACR 2011; Poster #2368.
What is the Optimal Definition for Duration of Sustained
Remission in ANCA-Associated Vasculitis?
• Objective: To arrive at a definition for duration
of sustained remission in AAV that best
discriminates b/w more or less effective
treatments
• Method: Data drawn from the IMPROVE trial:
AZA vs. MMF
 Tested periods from 1 month to 36 months
and assessed risk ratio
• Results:
 6 months resulted in highest RR (1.6)
 Any interval between 4-13 months was able to
discriminate between the 2 regimens
Tomasson G, et al. Presented at ACR 2011; Poster #2369.
Mental Health as a Predictor of Disease Flare
in Wegener’s Granulomatosis
• Objective: To determine if stress contributes to
disease flare
• Method: Assessed patients in WGET trial who
had achieved remission (6 months)
 Assessed SF-36 scores (MCS, PCS)
• Results:
 5-point lower MCS score at the preceding visit
was associated with a 19% increased
likelihood of having a flare at the current visit
• Conclusion: Mental health may be an important
independent factor affecting the likelihood of
future disease flares
Davids ML, et al. Presented at ACR 2011; Poster #2371.
Fibromyalgia and Soft Tissue
Disorders
Highlights of an ACR Concurrent
Abstract Session, Monday,
November 7
Summarized by Dr. Robert Offer
221
List of Presentations in this Session
Speaker
Title
Ste-Marie PA
Continued Opioid Use in Fibromyalgia
Is Associated with Negative Health
Related Outcomes
1605
Wolfe F
An 11-Year Longitudinal Study of
Pharmacologic Therapy in
Fibromyalgia
1610
Concurrent abstract session. Fibromyalgia
and Soft Tissue Disorders. ACR 2011; Mon., Nov. 7.
Abstract #
222
Impact of Continued Opioid Use for
Fibromyalgia
• Objective: To examine the outcome in FM
patients stratified according to opioid use in a
longitudinal study
• Subjects: 159 patients with FM in a prospective
cohort
• Variables assessed:
 Demographics and disease information
 Patient Global Impression of Change (PGIC)
 Employment and disability status
 FIQ, HAQ, PDI, Pain and Global VAS,
depression & anxiety
Ste-Marie PA, et al. Presented at ACR 2011; Presentation #1605.
Impact of Continued Opioid Use for
Fibromyalgia
ALL
n=131
Opioid users
n=43
Non-users
n=88
p
value
Employed, n (%)
39 (30)
11 (26)
28 (32)
NS
Disability, n (%)
42 (32)
16 (37)
26 (30)
NS
PAIN
Pain VAS ±SD
6.4 ± 2.3
6.9 ±2.2
6.2 ±2.4
NS
MPQ ±SD
42 ± 15
46 ±15
40 ±15
0.03
Body Map ±SD
27 ± 10
28 ±9
26 ±11
NS
FUNCTION
FIQ ±SD
66 ± 18
72 ±15
63 ±18
0.005
PDI ±SD
37 ± 15
41 ±14
34 ±16
0.018
HAQ ±SD
1.14 ± 0.66
1.23 ±0.67
1.09 ±0.65
NS
Patient global VAS ±SD
6.4 ± 2.4
7.1 ±2.3
6.1 ±2.4
0.025
AIMS anx ±SD
6.1 ± 1.9
6.4 ±1.7
6.0 ±2.0
NS
AIMS dep ±SD
5.0 ± 1.6
5.2 ±1.4
4.9 ±1.7
NS
Ste-Marie PA, et al. Presented at ACR 2011; Presentation #1605.
11-year Longitudinal Study of
Pharmacotherapy for Fibromyalgia: Analgesics
N=2870, assessed q6mo
Wolfe F, et al. Presented at ACR 2011; Presentation #1610.
11-year Longitudinal Study of Pharmacotherapy for
Fibromyalgia: Centrally Acting Agents
N=2870, assessed q6mo
Wolfe F, et al. Presented at ACR 2011; Presentation #1610.
11-year Longitudinal Study of Pharmacotherapy for
Fibromyalgia: Centrally Acting Agents
N=2870, assessed q6mo
Wolfe F, et al. Presented at ACR 2011; Presentation #1610.
Autoimmune Myopathies
Highlights of Various ACR
Sessions, November 6-9
Summarized by Dr. Yves Troyanov
228
List of Presentations in this Section
Speaker /
Primary Author
Title
ChristopherStine L
Statin Myopathies: Emerging Concepts
NA
Fiorentino D
Dermatomyositis Skin Disease: Novel Phenotypes in
Diagnosis, Prognosis, and Therapy
NA
Nakashima R
Clinical Features and Treatment of Dermatomyositis
Patients with Anti-CADM-140 (melanoma
differentiation-associated protein 5: MDA5) Antibody;
Recommendation of Combined Immunosuppressive
Therapy with Intensive Intravenous
Cyclophosphamide
225
Various ACR 2011 Sessions; November 6-9.
Abstract #
229
List of Presentations in this Section
Speaker /
Primary Author
Title
Ceribelli A
Anti-MJ/NXP-2 Antibodies Are the Most Common
Specificity in a Cohort of Adult Caucasian Patients
with Dermatomyositis
231
Satoh M
Transcription Intermediary Factor (TIF)-1β Is a New
Dermatomyositis Autoantigen
228
AgudeloHernandez A
Clinical Features and Survival in Anti-PL-7
Autoantibody Positive Myositis Patients From a
Single Tertiary Care Center
229
Paik JJ
Features of Acute Denervation in Scleroderma
Myopathy
1463
Various ACR 2011 Sessions; November 6-9.
Abstract #
230
Statin-induced Immune Myopathy
• What is the clinical, serological and pathological
phenotype of statin-induced immune myopathy?
 Adults over 50 years
 Exposure to atorvastatin
 Progressive CK elevation despite cessation of
statin
 No Raynaud's, arthritis or ILD
 High CKs
 Necrosis on muscle biopsy
 Anti-HMGCR autoantibody on ELISA testing
 Anti-200-100 autoantibody on IPP testing
Christopher-Stine L. Clinical Symposium " Emerging Concepts in the
Inflammatory Myopathies ". Presented at ACR 2011.
Anti-MDA5 Dermatomyositis:
Specific Dermatologic Features
•
•
•
•
Palmar papules
Skin ulcerations (digital, Gottron's, elbows)
Severe alopecia
Thickened red plaques on lateral aspects of
index fingers
• Digital necrosis or ischemia
• Gum and oral pain
• Gum and oral ulcerations
Fiorentino D. Clinical Symposium " Emerging Concepts in the
Inflammatory Myopathies ". Presented at ACR 2011.
Anti-MDA5 Dermatomyositis:
Extracutaneous Features
•
•
•
•
Mild muscle involvement (normal or low CKs)
Arthritis
Hand swelling
Interstitial lung disease
 Non-UIP, NSIP and DAD pattern on hrCT
 Random distribution of peripheral and
peribronchovascular consolidations and nonseptal linear or plate-like opacities
Fiorentino D. Clinical Symposium " Emerging Concepts in the
Inflammatory Myopathies ". Presented at ACR 2011.
Anti-MDA5 Dermatomyositis:
Laboratory Features
•
•
•
•
•
•
•
•
•
Evidence of macrophage activation
High ferritin
Cytopenias (lymphopenia under 900/mL)
Hypertriglyceridemia
High LDH
High LFTs
Negative ANA
Anti-MDA5 on ELISA testing
Anti-140 autoantibody on IPP testing
Fiorentino D. Clinical Symposium " Emerging Concepts in the
Inflammatory Myopathies ". Presented at ACR 2011.
Anti-MDA5 Dermatomyositis:
Immunosuppressants + High-dose Prednisone
• Objective: To assess the efficacy of combined
immunosuppressive therapy for anti-MDA5
dermatomyositis
• Subjects: 24 anti-MDA5-positive patients and 23
anti-MDA5-negative patients
• Method: Evaluation of the effect of intensive
regimen high dose prednisone, oral
cyclosporine and i.v. cyclophosphamide given
to anti-MDA5 patients
• Results: Survival rate of the intensive regimen
group was higher than that of the others (57.1%
vs. 28.6%)
Nakashima R, et al. Presented at ACR 2011; Poster #225.
Clinical Phenotype of Anti-MJ
Dermatomyositis
Anti-MJ (+)
n = 10
Anti-MJ (-)
n = 48
40%
23%
Mean age, yrs (±SD)
37.6 (±12)
54.6 (±14.8)
DM/PM/overlap
80/ 20/ 0 %
40/ 48/ 3 %
DM 0.03
Heliotrope rash
60%
19%
0.01
Calcinosis
30%
6%
0.06
Heart involvement
0%
27%
Interstitial lung disease
0%
33%
Elevated CPK at last visit
0%
25%
Male
Ceribelli A, et al. Presented at ACR 2011; Poster #231.
p value
0.05
Clinical Phenotype of Anti-TIF-1β
Dermatomyositis
• 4 patients identified from sera of 2200 patients
 3 patients with dermatomyositis, 1 with
undifferentiated connective tissue disease
• Characteristics:
 Mild CK elevation and myopathy
– 654, 341*, 314 and 2414*
 Mild DM rashes
– G, no rash, S, G + H + S
 No ILD
 Positive ANA
 Anti-120 autoantibody on IPP testing
Satoh M, et al. Presented at ACR 2011; Poster #228.
Anti-PL7 Myositis: Key Clinical Features
• Predominantly pulmonary presentations
• Pulmonary hypertension is a common
complication
• Survival is severely compromised
Agudelo-Hernandez A, et al. Presented at ACR 2011; Poster #229.
Scleroderma Myopathy: Key Features
• 29 patients
 Mean CK = 2078 (SD 3544)
 EMGs (N-M-I) = 4% - 38.4% - 57.6%
 MRI = edema in 94.4%
 Autoantibodies:
– ACA (18.5%)
– TOPO-1 (3.8%)
– RNA-Polymerase III (15.3%)
– U1-RNP (25.9%)
Paik JJ, et al. Presented at ACR 2011; Poster #1463.
Scleroderma Myopathy: Muscle Biopsy
Feature
Inflammation only
Necrosis only
Result
0
8 (27.6%)
Inflammation and necrosis
14 (28.2%)
Esterase positivity
(marker of acute denervation)
14 (48.2%)
Presence of fibrosis with
inflammation and/or necrosis
11 (37.9%)
Paik JJ, et al. Presented at ACR 2011; Poster #1463.