1 acr 2011 medical passport highlights of acr 2011 chicago, il november 2011
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ACR 2011 Medical Passport
Highlights of ACR 2011Chicago, IL
November 2011
Medical Passport Program-ACR 2011 2
Faculty
Hector Arbillaga, MD
Philip Baer, MD
Majed Khraishi, MD
Clode Lessard, MD
Robert Offer, MD
Peter Panopalis, MD
Janet Pope, MD
Anthony Russell, MD
Yves Troyanov, MD
Edith Villeneuve, MD
3
Disclosure
Copyright 2011 STA HealthCare Communications Inc. All rights reserved. This program is published by STA HealthCare Communications Inc. as a professional service funded by Bristol-Myers Squibb Canada Co. The information and opinions contained herein reflect the views and experience of the authors and not necessarily those of Bristol-Myers Squibb Canada Co., or STA HealthCare Communications Inc. Any products mentioned herein should be used in accordance with the prescribing information contained in their respective product monograph.
RA Treatment: Existing Disease-modifying Antirheumatic Drugs and Corticosteroids
Hector Arbillaga, MD
Rheumatoid Arthritis Clinical Aspects Peter Panopalis, MD
Clinical Features of RA; Disease Severity; Outcomes Research and Metrology
Robert Offer, MD
RA Treatment: Small Molecules, Biologics and Gene Therapy
Majed Khraishi, MD
Clode Lessard, MD
Edith Villeneuve, MD
Looking Ahead to Kinase Inhibition in Rheumatoid Arthritis
Anthony Russell, MD
4
Outline
Imaging of Rheumatic Disease Edith Villeneuve, MD
ACR Plenary Session: Discovery 2011 Robert Offer, MD
ACR Late-breaking Abstracts Janet Pope, MD
Spondylarthropathies: Recent Insights Majed Khraishi, MD
Impact of Environmental Healthon Autoimmunity
Hector Arbillaga, MD
Osteoporosis and Metabolic Bone Disease: Clinical Aspects and Pathogenesis
Philip Baer, MD
Orthopedics, Low Back Pain, and Rehabilitation
Anthony Russell, MD
5
Outline
Systemic Sclerosis (SSc), Fibrosing Syndromes and Raynaud's - Clinical Aspects and Therapeutics
Clode Lessard, MD
Janet Pope, MD
Complicated Raynaud's Phenomenon Philip Baer, MD
Vasculitis Peter Panopalis, MD
New Developments in the Clinical Evaluation, Immunology and Treatment of Myositis
Yves Troyanov, MD
Emerging Concepts in the Inflammatory Myopathies
Yves Troyanov, MD
6
Outline
7
RA Treatment: Existing Disease-modifying Antirheumatic Drugs
and Corticosteroids
Highlights of the ACR Concurrent Abstract Session held Tuesday,
November 8Summarized by Dr. Hector Arbillaga
List of Presentations in this Section
Speaker Title Abstract #
Villeneuve E
Preliminary Results of a Multicentre Randomised Controlled Trial of Etanercept and Methotrexate to Induce Remission in Patients with Newly Diagnosed Inflammatory Arthritis
2465
8Concurrent Abstract Session—RA Treatment: Existing Disease-modifyingAntirheumatic Drugs and Corticosteroids. ACR 2011; Tues., Nov. 8.
MTX + Etanercept or Placebo in RA:Design of The EMPIRE Study
9Villeneuve E, et al. Presented at ACR 2011; Presentation #2465.
MTX + Etanercept or Placebo in RA:Clinical Remission* in the EMPIRE Study
10
*No tender or swollen jointsNB: 5(9.1%) stopped biologics due to sustained remissionVilleneuve E, et al. Presented at ACR 2011; Presentation #2465.
Week 2 Week 26 Week 520
5
10
15
20
25
30
35
2
24
29
11
16
31
MTX + placebo MTX + etanercept
% o
f p
atie
nts
p = 0.051
p = ns
p = ns
Does the Presence of ACPA Impact on Efficacy? DAS28 Remission at Week 52 (EMPIRE Study)
11Villeneuve E, et al. Presented at ACR 2011; Presentation #2465.
MTX + Etanercept or Placebo in RA:Conclusions from the EMPIRE Study
12Villeneuve E, et al. Presented at ACR 2011; Presentation #2465.
• Rapid clinical responses were demonstrated with MTX + ETN combination therapy
• At one year, large proportions of both remission and LDAS were achieved in both groups
• Trend toward earlier clinical responses were seen in the ACPA-positive patients
• High response rates to MTX still need to be explained
13
Rheumatoid Arthritis: Clinical Aspects
Highlights of ACR Poster and Concurrent Abstract Sessions,
Sunday November 6Summarized by Drs. Robert Offer and
Peter Panopalis
List of Presentations in this Section
Speaker / Primary Author
Title Abstract #
Bili A
Prolonged Hydroxychloroquine Use Is Associated with Decreased Incidence of Cardiovascular Disease in Rheumatoid Arthritis Patients
1168
Walker CPStatin 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 GADifferential Predictors of Mixed and Fully Calcified Coronary Plaques in Coronary Artery Disease-Naïve Patients with Rheumatoid Arthritis
759
14Poster and Concurrent Abstract Sessions: Rheumatoid Arthritis: Clinical Aspects. ACR 2011; Sun., Nov. 6
List of Presentations in this Section (cont'd)
Speaker / Primary Author
Title Abstract #
van Sijl AMOutward Carotid Arterial Wall Remodelling in Rheumatoid Arthritis: A Case-Control Study
760
Berglin EHComparison of the 1987 ACR and 2010 ACR/EULAR Classification Criteria for Rheumatoid Arthritis in Clinical Practice
312
de Hair MJThe 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
15Poster and Concurrent Abstract Sessions:Rheumatoid Arthritis: Clinical Aspects. ACR 2011; Sun., Nov. 6
List of Presentations in this Section (cont'd)
Speaker / Primary Author
Title Abstract #
Nicolau JPerformances of the 2010 ACR/EULAR Classification Criteria of Rheumatoid Arthritis: Comparison with 1987 ACR Criteria in the Community-Based Vera Cohort
315
Ortiz Garcia AMComparison of the 1987 and 2010 Classification Criteria for Rheumatoid Arthritis in a Population of Patients with Early Arthritis
319
Bergman MJRoutine 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 NTo Screen Remission without Formal Joint Count: Analysis of Routine Assessment of Patient Index Data 3 in Japanese National Database
345
16Poster and Concurrent Abstract Sessions:Rheumatoid Arthritis: Clinical Aspects. ACR 2011; Sun., Nov. 6
Prolonged Hydroxychloroquine Use in RAis Associated with Decrease in CVD
Bili A, et al. Presented at ACR 2011; Poster #1168.
72% reductionp<0.001 vs. never use
Prolonged Hydroxychloroquine Use in RAis Associated with Decrease in CAD
Bili A, et al. Presented at ACR 2011; Poster #1168.
73% reductionp<0.001 vs. never use
Statin Use is Associated with Decreased CAD Events in Patients with RA and no CVD
• Objective: To examine the association of statin use with incident CAD in an inception cohort of RA patients
• Method: Inception cohort of RA patients 1881 patients with newly diagnosed RA, but no pre-existing
CVD Primary outcome: Time to CAD Secondary outcome: Time to CVD
• Key results: 550 patients were included In RA patients without CVD, statin use was associated with
a 4% per month decrease in incident CAD For patients using statins for >17 months, the risk of
incident CAD decreased by 70%
Walker CP, et al. Presented at ACR 2011; Poster #1160.
Bisphosphonates and CAD
TreatmentOdds 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
Non-calcified Mixed Full calcified0
10
20
30
40
50
60
70
8070
14 16
51
28
21
Controls RA
% o
f af
fect
ed s
egm
ents
Karpouzas GA, et al. Presented at ACR 2011; Presentation #759.
p = 0.004
p = 0.0002
Calcified Coronary Artery Plaques in RA: Key Findings
• Predictors of higher mixed plaque prevalence: DAS28-3 ≥ 3.2 High CRP
• Treatment with a TNF-α inhibitor was associated with a 70% lower risk for mixed plaque presence Even in the absence of good clinical response
Karpouzas GA, et al. Presented at ACR 2011; Presentation #759.
Outward Carotid Arterial WallRemodelling in RA: A Case-Control Study
• Objective: To assess arterial remodelling in RA• Method: B-mode carotid ultrasonography was
performed in 96 RA and 274 healthy controls Investigators assessed various parameters
such as intima-media thickness (IMT), inter-adventitial diameter (IAD) and lumen diameter (LD)
• Results: RA is associated with outward remodelling
• Interpretation: This is relevant in view of the association between outward remodelling and plaque instability and rupture
van Sijl AM, et al. Presented at ACR 2011; Presentation #760.
Comparisons of the 1987 ACR and 2010 ACR/EULAR Classification Criteria in Early Arthritis
• The 2010 ACR/EULAR criteria had higher sensitivity but lower specificity than 1987 ACR criteria in a cohort of early arthritis 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.
25
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.
The Use of RAPID3 for aTreat-to-Target Strategy
• Background: RAPID3 is a composite measure of disease activity, requiring only 3 patient self-reported measures: Physical function, pain and patient estimate of global disease status
• Method: The authors compared RAPID3 to DAS28 and to CDAI in a treat-to-target approach in a usual care setting
• Findings: RAPID3 appears similar to DAS28 and CDAI for recognition of low activity/severity or remission versus high activity/severity to guide a treat-to-target strategy for RA
Bergman MJ, et al. Presented at ACR 2011; Presentation #331.
Use of the RAPID3 to Assess Remission
N=4479�� Sensitivity(%)
Specificity(%)
SDAI remission 91 93
CDAI remission 89.3 93.8
DAS28 remission 76.9 84.7
RAPID3 < 2 90.5 79.4
RAPID3 < 3 95.4 31.6
Yokogawa N, et al. Presented at ACR 2011; Presentation #345.
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Clinical Features of Rheumatoid Arthritis; Disease Severity; Outcomes Research and
MetrologyHighlights of an ACR Poster
Session, Tuesday, November 8Summarized by Dr. Robert Offer
List of Presentations in this Section
Speaker Title Abstract #
Knevel RGenetic Predisposition of the Severity of Joint Destruction in Rheumatoid Arthritis; A Population Based Study.
2136
Clowse MEContraception Use in Women with Rheumatoid Arthritis
2109
29Poster Session: Clinical Features of Rheumatoid Arthritis; Disease Severity;Outcomes Research and Metrology. ACR 2011; Tues., Nov. 8.
Susceptibility to RA is Partly Inherited. What About Severity of RA?
• Objective: To evaluate whether the severity of joint destruction in RA is heritable
• Method: Data analysis of records from 325 patients in an Icelandic database with complete radiographs of hand and feet and relevant genealogic information
• Results: Significant associations between degree of relatedness and similarity in joint destruction rates were observed
Knevel R, et al. Presented at ACR 2011; Poster #2136.
Are Women on RA Medications Using Contraception Appropriately?
Contraceptive method Failure rate* Use in this cohort†
Ineffective 36 (34%)
No method 85% 16
Abstinence 11
Withdrawal 27% 4
Rhythm method 25% 3
Condoms 15% 9
Effective 24 (22.6%)
Estrogen-combination pills 8% 17
Progestin-only pills 5% 2
Depo-Provera® injection 3% 1
Intra-uterine device 0.2% 4
Sterilization 46 (43.4%)
*% of women who conceive using this method over a year†Some women use multiple forms of contraceptionClowse ME, et al. Presented at ACR 2011; Poster #2109.
FDA Pregnancy Categories: RA Medications
Clowse ME, et al. Presented at ACR 2011; Poster #2109.
FDACategory Definition DMARDs and Biologics
A Extensive human safety data demonstrating no fetal risk
BReassuring animal data with little/no human data to confirm this; OR animal studies show risk but human data showing no risk
TNF inhibitorsSulfasalazine (D at term)
CEither no animal studies or animal studies suggest no risk, no human data to confirm this
HydroxychloroquineAbataceptRituximab
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
MethotrexateLeflunomide
Women taking
medication
Contraception
Ineffective Effective Sterilization
Class B
TNFi 56 (53%) 23 (41%) 14 (25%) 19 (34%)
SSZ 6 (6%) 1 (17%) 2 (33%) 3 (50%)
Class C
HCQ 20 (19%) 6 (30%) 7 (35%) 7 (35%)
ABA or RTX
13 (12%) 3 (23%) 0 10 (77%)
Class X
MTX or LEF
59 (56%) 17 (28%) 14 (23%) 28 (48%)
Contraceptive Use by RA Medication
Clowse ME, et al. Presented at ACR 2011; Poster #2109.
Are women on RA medications using contraception appropriately? Conclusions
• Almost half of women with RA in this cohort took FDA class X medications 28% of these women were using ineffective
contraception, leaving them at high risk for pregnancy
• 5-fold more women using ineffective contraception had a prior elective termination than either women using effective contraception or sterilization
• This study highlights the importance of contraceptive education and prescription by rheumatologists to ensure that patients taking potentially teratogenic medications do not become pregnant
Clowse ME, et al. Presented at ACR 2011; Poster #2109.
35
RA Treatment: Small Molecules, Biologics and Gene Therapy
Highlights of ACR Poster Sessions, November 6-8
Summarized by Drs. Majed Khraishi,Clode Lessard, Robert Offer, Janet Pope and
Edith Villeneuve
List of Presentations in this Section
Speaker / primary author Title Abstract #
Pope JThe 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
36Poster Sessions—RA Treatment: Small Molecules, Biologicsand Gene Therapy. ACR 2011; Nov. 6-8.
List of Presentations in this Section (cont'd)
Speaker / primary author Title Abstract #
Emery P
Evaluation of the Association Between Disease Activity and Risk of Serious Infections in Subjects with Rheumatoid Arthritis When Treated with Etanercept or DMARDs
429
Yonemoto Y Direct Comparison of Four Biologics in Biologic-naïve Rheumatoid Arthritis Patients 1236
Strangfeld A Impact of Different Biologic Agents on the Improvement of Fatigue 461
Meissner BReal-World Switching Patterns in RA Patients Receiving Abatacept, Adalimumab, Etanercept or Infliximab As Second-Line Biologic Therapy
2198
37Poster Sessions—RA Treatment: Small Molecules, Biologicsand Gene Therapy. ACR 2011; Nov. 6-8.
List of Presentations in this Section (cont'd)
Speaker Title Abstract #
Burmester JR
Tofacitinib (CP-690,550), An Oral Janus Kinase Inhibitor, in Combination with Methotrexate, in Patients with Active Rheumatoid Arthritis with An Inadequate Response to Tumor Necrosis Factor-Inhibitors: A 6-Month Phase 3 Study
718
Yamanaka H
Tofacitinib (CP-690,550), An Oral Janus Kinase Inhibitor, As Monotherapy or with Background Methotrexate in Japanese Patients with Rheumatoid Arthritis: A Phase 2/3 Long-Term Extension Study
1215
Vanhoutte FGLPG0634 Shows Selective Inhibition of JAK1 and Maintained JAK-STAT Suppression in Healthy Volunteers
2210
38Poster Sessions—RA Treatment: Small Molecules, Biologicsand Gene Therapy. ACR 2011; Nov. 6-8.
List of Presentations in this Section (cont'd)
Speaker Title Abstract #
Urata Y
Treating to Target Matrix Metalloproteinase 3 Normalisation Together with Disease Activity Score Below 2.6 Yields Better Effects Than Each Alone In Rheumatoid Arthritis Patients: Treating to Twin Targets; T-4 Study
1207
Matsubara T SNP Algorithms for Prediction of Efficacy and Adverse Events of Abatacept 1263
39Poster Sessions—RA Treatment: Small Molecules, Biologicsand Gene Therapy. ACR 2011; Nov. 6-8.
The Effectiveness of Abatacept in a Large RA Real-World Practice
• Background: Long-term, real-world effectiveness data in
RA patients using abatacept in a large multi-centre cohort are lacking
There is a high drop out rate with some biologics, such as TNF inhibitors, within the first two years of treatment
NNT for improving HAQ in RA for TNFi is 1.94
Pope J, et al. Presented at ACR 2011; Poster #1222.
The Effectiveness of Abatacept in a Large RA Real-World Practice
• Objective: 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. non-
exposed patients
Pope J, et al. Presented at ACR 2011; Poster #1222.
Abatacept in Real-World Practice:Baseline Characteristics and Disposition
Parameter Post DMARDN=369
Post TNFiN=1,402
Total CohortN=1,771 p Value
Mean age, years (SD) 58.80 (13.65) 57.28 (13.10) 57.60 (13.23) 0.0496
Mean time since diagnosis, years (SD) 13.25 (10.83) 17.36 (10.92) 16.53 (11.02) <0.001
Female gender, n (%) 260 (70.46) 1,107 (78.96) 1,367 (77.19) <0.001
Disease Severity,n (%)
Mild 1 (0.27) 4 (0.29) 5 (0.28)
0.736 Moderate 22 (5.96) 104 (7.42) 126 (7.11)
Severe 346 (93.77) 1,291 (92.08) 1,637 (92.43)
NA 0 (0.00) 3 (0.21) 3 (0.17)
Mean durability of treatment, months (SD) 26.12 (0.86) 25.75 (0.58) 26.79 (0.53) < 0.001
Pope J, et al. Presented at ACR 2011; Poster #1222.
Abatacept in Real-World Practice:Change in HAQ Scores
Baseline 12 months 24 months 36 months0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
Post DMARD Post TNFi Total cohort
Mea
n H
AQ
Sco
re
Pope J, et al. Presented at ACR 2011; Poster #1222.
Abatacept in Real-World Practice:Overall Treatment Durability
Pope J, et al. Presented at ACR 2011; Poster #1222.
Abatacept in Real-World Practice:Treatment Durability by Prior Treatment
Pope J, et al. Presented at ACR 2011; Poster #1222.
Abatacept in Real-World Practice:Achievement of Clinically Important HAQ Change
Pope J, et al. Presented at ACR 2011; Poster #1222.
MCID
# of prior biologics
OR 95% CI
pvalue
NNT (1/ARR)
Modified NNT 0
biologics
Modified NNT ≥ 1 biologic
0 ≥1
Yes, n (%)
213 (70.1)
806 (71.4)
0.940.71 to
1.240.65 75.5 1.43 1.40
No, n (%)
91 (29.9)
323 (28.6)
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.
48
Comparative effectiveness and time to response among adalimumab, abatacept,
etanercept and infliximab for the treatment of RA in a real world routine
care registry
Yusuf Yazici, MD, Maria F Filopoulos, MD,
Christopher J Swearingen, PhD
NYU Hospital for Joint Diseases, New York, USA,
University of Arkansas for Medical Sciences, Little Rock, AR
Yazici et al. ACR 2011
49
Method
Prospective analysis from NYU Arthritis Registry Monitoring Database (ARMD) since 2005 in all patients seen in routine care. Each patient in this setting completes 1-page MDHAQ at every visit Usage of the biologic medications abatacept, adalimumab,
etanercept and infliximab along with self-reported disease activity and clinic measures were abstracted.
Treatments were considered to be independent of each other as no individual received biologic medications in combination.
Adapted from Yazici et al. ACR 2011
50
Method
Time to first response defined as Improvement in RAPID3 of at least 3.6 (clinically important
difference).
Change from biologic medication initiation to first response for self-reported disease activity and clinic measures was estimated.
For those individuals with no response, time to last follow-up was calculated.
Differences in time to first response between biologic medications were estimated using Cox proportional hazards model.
Adapted from Yazici et al. ACR 2011
51
RAPID3 component scores at baseline
Adapted from Yazici et al. ACR 2011
52
Cumulative incidence of time to RAPID3 >3.6 response adjusted for age and disease duration
Adapted from Yazici et al. ACR 2011
53
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.
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
Emery P, et al. Presented at ACR 2011; Poster #429.
HR for serious infection 95% CI
Etanercept vs. DMARD 1.066 0.86 to 1.32
DAS (per integer increase) 1.156 1.06 to 1.26
Direct Comparison of 4 Biologicsin Biologic-Naïve RA Patients
• 144 biologic-naïve patients starting a biologic from July 2008 onward
Yonemoto Y, et al. Presented at ACR 2011; Poster #1236.
Baseline Characteristic IFX (n=37) ETN (n=39) TCZ (n=27) ADA (n=39) p
Male, % 16 21 22 28 0.65
Age, years 59 59 63 60 0.33
RA duration, months 105 131 149 132 0.28
Concomitant MTX, % 100 54 41 87 <0.01
MTX dosage, mg/wk 6.6 6.3 5.3 6.2 <0.01
Concomitant PSL, % 84 67 74 59 0.11
PSL dosage, mg/day 4.5 4.8 4.8 5.0 0.77
CRP (mg/dL) 2.66 2.81 4.27 2.62 <0.01
ESR (mm/hr) 53 54 71 52 0.41
MMP-3 (ng/dL) 275.2 241.0 315.4 286.0 0.74
DAS-28 (ESR) 4.9 4.8 5.5 4.8 0.73
DAS-28 (CRP) 3.9 3.8 4.6 3.9 <0.05
Direct Comparison of 4 Biologicsin 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 Biologicsin 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?
TreatmentNo. of
patients
No fatigue at 6 months
Significant improvement
Adj. OR 95% CI Adj. OR 95% CI
DMARD 1,059 Ref. - Ref. -
Etanercept 1,272 1.7* 1.3 to 2.1 2.0* 1.7 to 2.5
Infliximab 507 1.6* 1.2 to 2.2 1.7* 1.3 to 2.2
Adalimumab 1,407 1.4* 1.1 to 1.7 1.8* 1.4 to 2.2
Rituximab 783 1.3 0.9 to 1.8 1.6* 1.2 to 2.1
Abatacept 180 1.1 0.7 to 1.9 1.4 0.9 to 2.1
Tocilizumab 222 1.6* 1.0 to 2.4 2.0* 1.4 to 2.9
*Statistically significant difference vs. DMARD groupStrangfeld A, et al. Presented at ACR 2011; Poster #461.
Fatigue: Are All Biologics Equal?
Strangfeld A, et al. Presented at ACR 2011; Poster #461.
7
6
5
4Baseline 3 months 6 months
DMARD
Etanercept
Infliximab
Adalimumab
Rituximab
Abatacept
Tocilizumab
Mea
n l
evel
of
fati
gu
e
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
61
Analysis of pharmacy data in the USMeissner B, et al. Presented at ACR 2011; Poster #2198.
Tofacitinib in TNF Failures:The ORAL Step Study
• At Month 3, all placebo patients blindly advanced to tofacitinib 5 or 10 mg BID
• Primary assessments: ACR20, HAQ-DI, DAS28(ESR) <2.6, safety and tolerability
Burmester JR, et al. Presented at ACR 2011; Presentation #718.
Tofacitinib in TNF Failures(ORAL Step Study) : Prior DMARD Use
n (%)
PBO 5n=66
PBO 10n=66
5 mgn=133
10 mg BID n=134
Prior TNFi 66 (100) 66 (100) 132 (99.2)* 132 (98.5)†
AdalimumabCertolizumabEtanerceptGolimumabInfliximab
36 (54.5)7 (10.6)
29 (43.9)2 (3.0)
27 (40.9)
42 (63,6)4 (6.0)
28 (42.4)5 (7.6)
16 (24.2)
65 (48.9)9 (6.8)
65 (48.9)5 (3.8)
56 (42.1)
74 (55.2)9 (6.7)
57 (42.5)8 (6.0)
42 (31.3)
Other biologics 4 (6.1) 10 (15.2) 21 (15.8) 11 (8.2)
Non-biologic DMARDs other than MTX
16 (24.2) 17 (25.8) 53 (39.8) 37 (27.6)
*One patient had been previously treated with a biosimilar version of etanercept;† Two patients had no previous treatment with TNFi (MTX, n=1; MTX + sulfasalazine, n=1)Burmester JR, et al. Presented at ACR 2011; Presentation #718.
Tofacitinib in TNF Failures: ACR20 Responses at Month 3
Placebo Tofacitinib 5 mg Tofacitinib 10 mg0
10
20
30
40
50
60
24.4
41.7*
48.1†
% o
f p
atie
nts
*p≤0.05; †p<0.0001Burmester JR, et al. Presented at ACR 2011; Presentation #718.
Tofacitinib in TNF Failures: ACR20 Responses at Month 3 by Previous TNFi Exposure
1 Prior TNFi 2 Prior TNFis 3 Prior TNFis0
10
20
30
40
50
60
30.6
10.8
22.2
43.4*
37.8* 36.4
48.353.3†
41.7
Placebo Tofacitinib 5 mg Tofacitinib 10 mg
% o
f p
atie
nts
*p≤0.05; †p<0.0001Burmester JR, et al. Presented at ACR 2011; Presentation #718.
Tofacitinib in TNF Failures: Laboratory Tests
Month 3 Month 6
PBO 5 mg BID
10 mg BID
PBO 5
PBO 10
5 mg BID
10 mg BID
LS mean change from baseline
Neutrophil count, 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<0.0001Burmester 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
68Yamanaka H, et al. Presented at ACR 2011; Poster #1215.
Early Research with GLPG0634,A Novel, Selective JAK1 Inhibitor
• Key findings: GLPG0634 potently inhibits JAK1 with a 30-fold
selectivity over JAK2 in whole blood assays In healthy volunteers, GLPG0634 is well tolerated
in the pharmacologic active dose range PK/PD relationship is consistent with once-daily
dosing No signs indicative of anemia were observed after
10-days of dosing• Results support progression into efficacy
evaluation in RA patients
69Vanhoutte F, et al. Presented at ACR 2011; Poster #2210.
Research Presented at ACR 2011 With Possible Implications for Future Practice
• Treating to target MMP-3 together with DAS28 < 2.6 yields better results than each target alone in RA (Treating to Twin Targets [T-4] Study)1
• SNP algorithms predict efficacy and adverse events of 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.
71
Looking Ahead to Kinase Inhibition in Rheumatoid
Arthritis
Highlights of an ACR Clinical Symposium, Sunday, November 6
Summarized by Drs. Robert Offer and Anthony Russell
List of Presentations in this Section
Speaker Title
Genovese MCWhich Kinase Pathways are Important in Rheumatoid Arthritis and How Do We Decide What to Target?
Weinblatt MEWhat Does the Data Inform Us About Safety and Efficacy of Kinase Inhibitors?
Fleischmann RMWhere Will These Agents Fit into Our Treatment Paradigm?
72Clinical Symposium: Looking Ahead to Kinase Inhibition in Rheumatoid ArthritisACR 2011; Sun., Nov. 6 25.
73
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.
JAK SignallingJAK1 JAK2 JAK3 TYK2
Type I and Type IIcytokine receptors
Type II cytokinereceptors
Common γ chain elicits signals from IL-2 receptor family,IL-4 receptor family
Type 1 interferons α/β
Common γ chainelicits signals from IL-2receptor family,IL-4 receptor family
Receptors forhormonesErythropoietinThrombopoietinProlactinGrowth hormone
IL-2,4,7,9,15,21IL-12 receptorB1 subunit (IL-12/23)
IL-2, 4, 7, 9,15, 21GM-CSF receptor family (IL-3 R, IL-5R GM-CSFR)
gp130 receptor familyIL-6, 11, 27, 31
gp130 receptor familyIL-6, 11, 27, 31
Type 1 interferonsα/β
Type 1 interferonsα/β
Type II interferons γ Type II interferons γ
74
Genovese MC. Clinical Symposium " Looking Ahead to Kinase Inhibition in Rheumatoid Arthritis". Presented at ACR 2011.
75
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.
Tofacitinib (JAK Inhibitor): 6-week Phase II Study in RA in Monotherapy
76
Kremer JM, et al. Arthritis Rheum 2009; 60(7):1895-905.Cited by Weinblatt ME. Clinical Symposium " Looking Ahead to Kinase Inhibition in Rheumatoid Arthritis". Presented at ACR 2011.
Tofacitinib (JAK Inhibitor): Phase II Study in RA in Combination with MTX – Week 12 Results
77
Kremer JM, et al. Presented at ACR 2008; abstract L13.Cited by Weinblatt ME. Clinical Symposium " Looking Ahead to Kinase Inhibition in Rheumatoid Arthritis". Presented at ACR 2011.
Placebo + MTX 5 mg + MTX 15 mg + MTX 20 mg + MTX0
10
20
30
40
50
60
70
37.7
60.6 58.7 60.0
ACR20 ACR50 ACR70
% o
f p
atie
nts
wit
h A
CR
res
po
nse
s
Tofacitinib (JAK Inhibitor): Phase II Study in RA in Monotherapy – Week 12 Results
78
Kanik K, et al. Ann Rheum Dis 2009; 68(Suppl3):123. Cited by Weinblatt ME. Clinical Symposium " Looking Ahead to Kinase Inhibition in Rheumatoid Arthritis". Presented at ACR 2011.
Placebo Tofacitinib 5 mg
Tofacitinib 10 mg
Tofacitinib 15 mg
Adalimumab 40 mg eow
0
10
20
30
40
50
60
70
80
28.8
63.3
75.4 75.4
47.2
ACR20 ACR50 ACR70
% o
f p
atie
nts
wit
h A
CR
res
po
nse
s
Tofacitinib (JAK Inhibitor): Phase III Study in RA in Monotherapy – Week 12 Results
79
*p < 0.0001Fleischmann RM, et al. Presented at ACR 2010; abstract L8.Cited by Weinblatt ME. Clinical Symposium " Looking Ahead to Kinase Inhibition in Rheumatoid Arthritis". Presented at ACR 2011.
ACR20 Δ HAQ DAS Remission
Placebo 27% -0.2 4%
5 mg bid 60%* -0.5* 6%
10 mg bid 66%* -0.6* 9.6%
Tofacitinib (JAK Inhibitor): Phase III Study in RA in Combination with DMARDs – Week 24 Results
80
*p < 0.0001Kremer J, et al. Ann Rheum Dis 2011; 70(Suppl3):170.Cited by Weinblatt ME. Clinical Symposium " Looking Ahead to Kinase Inhibition in Rheumatoid Arthritis". Presented at ACR 2011.
ACR20 Δ HAQ DAS Remission
Placebo 31% -0.21 3%
5 mg bid 53%* -0.46* 11%
10 mg bid 58%* -0.56* 15%*
81
Tofacitinib (JAK Inhibitor) Combinedwith 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.
82
Tofacitinib Phase 3Monotherapy 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.
Tofacitinib Phase 3Monotherapy Study in RA
ACR20DAS28
remissionΔ HAQ
Placebo 28.3% 1.1% - 0.24
Tofacitinib 5 mg 51.5%* 7.3%* - 0.55*
Tofacitinib 10 mg 52.6%* 12.5%* - 0.61*
Adalimumab 40 mg eow 47.2%* 6.2%* - 0.49*
83
*p < 0.05 vs. placebovan Vollenhoven RF, et al. Presented at ACR 2011; Poster #408.Cited by Weinblatt ME. Clinical Symposium " Looking Ahead to Kinase Inhibition in Rheumatoid Arthritis". Presented at ACR 2011.
Tofacitinib Phase 3Monotherapy Study in RA
Treatment groupMonths 0-3 Months 3-6
AEs, n (%)SAEs , n
(%)AEs, n (%)
SAEs , n (%)
Tofacitinib 5 mg BID (n=204) 106 (52.0) 12 (5.9) 67 (32.8) 10 (4.9)
Tofacitinib 10 mg BID (n=201)
94 (46.8) 10 (5.0) 62 (30.8) 7 (3.5)
Adalimumab 40 mg SC Q2W (n=204)
105 (51.5) 5 (2.5) 68 (33.3) 6 (2.9)
Placebo (n=108 at mo. 3; n=59 mos. 3-6)
51 (47.2) 2 (1.9) 16 (27.1) 2 (3.4)
Placebo to tofacitinib 5 mg BID (n=28)
NA NA 7 (25.0) 0
Placebo to tofacitinib 10 mg BID (n=21)
NA NA 9 (42.9) 0
84
van Vollenhoven RF, et al. Presented at ACR 2011; Poster #408.Cited by Weinblatt ME. Clinical Symposium " Looking Ahead to Kinase Inhibition in Rheumatoid Arthritis". Presented at ACR 2011.
What are the Potential Concerns with Tofacitinib for the Clinician?
• Decrease in neutrophil counts (1.5% severe neutropenia with tofacitinib)
• Decrease in hemoglobin
• Significant elevation in serum creatinine without clinical impact
• Perturbation of lipid profile (↑HDL, ↑LDL)
• Elevated liver enzymes Placebo 17%, tofacitinib 28% (not
proportional to dosage)
van Vollenhoven RF, et al. Presented at ACR 2011; Poster #408.
Tofacitinib in RA: Open-Label, Long-Term Extension Studies up to 36 Months
86
Data are for tofacitinib 5 mg or 10 mg groups combined (n=3227)Wollenhaupt J, et al. Presented at ACR 2011; Poster #407.Cited by Weinblatt ME. Clinical Symposium " Looking Ahead to Kinase Inhibition in Rheumatoid Arthritis". Presented at ACR 2011.
Month 1 Month 360
10
20
30
40
50
60
70
8071.0 72.7
47.352.3
26.3
35.2
ACR20 ACR50 ACR70
% o
f p
atie
nts
wit
h A
CR
res
po
nse
s
Tofacitinib in RA: Open-Label, Long-Term Extension Studies up to 36 Months
• Mean tofacitinib exposure 309 days Total 3118 patient years
• Serious adverse events: 11.3/100 patient-years ↓ Hb ↑ ALT ↓ WBC Creat. ↑ 33% in 12% of patients
• Serious infectious events: 3.8/100 patient-years
87
n=3227,Wollenhaupt J, et al. Presented at ACR 2011; Poster #407.Cited by Weinblatt ME. Clinical Symposium " Looking Ahead to Kinase Inhibition in Rheumatoid Arthritis". Presented at ACR 2011.
Fostamatinib (Oral SYK Inhibitor) for RA
• Prodrug• Adverse effects are distinct from those of JAK
inhibition Diarrhea Headaches ↑ BP (controllable)
88
Weinblatt ME. Clinical Symposium " Looking Ahead to Kinase Inhibition in Rheumatoid Arthritis". Presented at ACR 2011.
Fostamatinib Phase II Trials in RA
MTX-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
Placebo (n=41)
VX-509
25 mg BID
(n=41)
50 mg BID
(n=41)
100 mg BID
(n=40)
150 mg BID
(n=41)
ACR20 29% 39% 61%* 65%† 66%†
ACR50 7.3% 17% 32%‡ 38%§ 49%§
ACR70 2.4% 7.3% 12% 18%¥ 22%¶
Δ DAS28-CRP -1.2 -1.7 -2.6§ -2.7§ -3.1§
90
*p=0.007; †p=0.002; ‡p=0.011; §p≤0.001 ¥p=0.029 ¶p=0.026Fleischmann R, et al. Presented at ACR 2011; Poster #L3
Safety of Kinase Inhibitors in RA
1. Tofacitinib phase II & III; 2. Fostamatinib phase II; 3. JAK 1/2 phase II.Cited by Fleischmann R. Clinical Symposium " Looking Ahead to Kinase Inhibition in Rheumatoid Arthritis". Presented at ACR 2011.
Tofacitinib1 Fostamatinib2 JAK 1/23
Number of patients 3030 552 136
Neutropenia
Elevated lipids
Elevated LFTs
↑ creatinine
Infection (URI, UTI, flu)
Opportunistic infection
Herpes Zoster
Diarrhea
Hypertension
Vertigo
Headache
Tofacitinib: What is Not Known in 2011
• What is the optimal starting dose of tofacitinib?
• Is 5 mg as effective as 10 mg?; Is 10 mg as safe as 5 mg?
• Does tofacitinib require MTX to be effective?
• Is the combination more effective than tofacitinib monotherapy?
• In MTX naïve patients:
• Is tofacitinib clinically the same as MTX or better?
• Is tofacitinib more likely to inhibit radiographic progression?
• If a patient fails to achieve a satisfactory response to 5 mg, will they respond to 10 mg?
• If a patient responds exceptionally well to 10 mg, will the patient continue to respond to 5 mg?
• If the patient goes into a true remission with tofacitinib, can it be withdrawn and the patient maintain benefit?
Fleischmann R. Clinical Symposium " Looking Ahead to Kinase Inhibition in Rheumatoid Arthritis". Presented at ACR 2011.
93
Imaging of Rheumatic Disease: Ultrasonography andDual-emission X-ray
Absorptiometry
Highlights of an ACR Concurrent Abstract Session, Sunday,
November 6Summarized by Dr. Edith Villeneuve
List of Presentations in this Section
Speaker Title Abstract #
El Miedany YM
Imaging As An Outcome Measure in Early Inflammatory Arthritis: Monitoring Disease Activity and Patients’ 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
94Concurrent Abstract Session:Imaging of Rheumatic Disease. ACR 2011; Sun., Nov. 6.
Ultrasound As An Outcome Measure in Early Arthritis: Study Design
• Subjects: 121 RA patients with sustained DAS28 remission for 6 months 65 on DMARDs, 56 on TNFi
• Methods: Data Collected
– PROMs (self-reported TJC)– US of 54 joints
• GS 0-3, PD 0-3, score per joint and total score
Treat-to-target of US remission (GS=0 and PD=0) Post-tx correlation with clinical outcome
measures were assessed
El Miedany YM. Presented at ACR 2011; Presentation #808.
Clinical Outcome Measuresin Ultrasound-assessed 28 Joints
El Miedany YM. Presented at ACR 2011; Presentation #808.
NB: Results were similar for 28- and 44-joint assessments
Variable US Findings p value
US arthritis US remission
DAS-28 2.31 (0.2) 2.32 (0.2) 0.986
TJC 28 (Physician) 1.24 (0.4) 1.23 (0.4) 0.942
TJC 28 (Patient) 1.91 (0.6) 1.3 (0.6) 0.022
SJC 28 1.19 (0.4) 0 (0.0) <0.001
PGA 11.9 (4.0) 9.6 (4.4) 0.028*
MS 10.7 (5.8) 8.1 (4.4) 0.021
Fn. Dis 0.56 (0.1) 0.73 (0.3) <0.001
QoL 0.50 (0.1) 0.73 (0.5) 0.026
ESR 18.9 (5.2) 19.9 (6.9) 0.554
CRP 9.7 (3.6) 9.6 (3.2) 0.860
Ultrasound As An Outcome Measure in Early Arthritis: Results
• US findings had an impact on management of patients: 31.1% DMARD dose ↑ 22% DMARD changed 21.6% biologic tx frequency ↑ 52.6% of affected scan joint received IA
steroid• At subsequent visit, US improvement was
associated with clinical outcome measures in response to treatment and helped maintained pts in remission
El Miedany YM. Presented at ACR 2011; Presentation #808.
Ultrasound As An Outcome Measure in Early Arthritis: Interpretation
• These data suggest that US may be a better tool to accurately evaluate clinical remission and may provide better treatment / outcomes for patients
• However, more stringent definition of remission is now recommended as the target
• Still need to demonstrate: Using US would have changed management Long-term outcomes of using US remission
as target compared to clinical remission
El Miedany YM. Presented at ACR 2011; Presentation #808.
Ultrasound As a Tool for Prediction of OngoingJoint 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 OngoingJoint Destruction: US Assessment
Yoshimi R. Presented at ACR 2011; Presentation #809.
• PD signals of 22 joints
• Each joint scored Grade 0-3)
• Total PD score = Sum of PD scoresof all 22 joints
Ultrasound for Prediction of Ongoing Joint Destruction: Patient Characteristics
Characteristic Total no. of cases = 31
Age 55.2 ± 13.4 years
Sex M: 4 cases F: 27 cases
Stage Ⅰ: 9 cases, : 15 cases, : 3 cases, : 4 casesⅡ Ⅲ Ⅳ
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
VariableNo radiographic
progressionRadiographicprogression
P value
Total PD score 0.87 ± 1.15 6.00 ± 6.44 0.0099
Total gray score 8.80 ± 5.78 12.6 ± 12.4 0.36
SJC 0.33 ± 0.79 1.29 ± 0.70 0.017
TJC 0.13 ± 0.34 0.57 ± 0.49 0.032
gVAS (mm) 9.40 ± 9.58 12.7 ± 4.40 0.41
ESR (mm/h) 10.2 ± 5.94 18.6 ± 16.2 0.11
CRP (mg/dl) 0.12 ± 0.15 0.08 ± 0.12 0.60
MMP-3 (ng/ml) 96.8 ± 110 62.1 ± 19.7 0.44
RF (U/ml) 73.8 ±89.5 86.8 ± 68.1 0.77
* No difference for age, disease duration, remission duration, MTX dose, Treatment between the 2 groups
Yoshimi R. Presented at ACR 2011; Presentation #809.
Total PD Score & Radiographic Progression
0 1 2 3 4 ≥50
3
6
9
No radiographic progressionRadiographic progression
Total PD Score
No
. of
pa
tie
nts
• X-ray progression is strongly associated with total PD score but also with TJC and SJC
• X-ray progression was not found in patients having total PD score of 0 or 1
Yoshimi R. Presented at ACR 2011; Presentation #809.
Ultrasound for Prediction of Ongoing Joint Destruction: Interpretation
• NPV of total PD score of 0 and 1 is very interesting
• Added value of PD > 1 in an individual patients still needs to be determined: Does is it add to physical exam? How do you differentiate a progressor from a
non-progressor in an individual patient?
Yoshimi R. Presented at ACR 2011; Presentation #809.
106
Discovery 2011
Highlights of an ACR Plenary Session, Sunday, November 6
Summarized by Dr. Robert Offer
Presentation in this Section
Speaker Title Abstract #
Bozaite-Gluosniene R
Reduced Cardiovascular Risk with Use of Methotrexate and Tumor Necrosis Factor-α Inhibitors in Patients with Rheumatoid Arthritis
719
107Plenary Session: Discovery 2011. ACR 2011; Sun., Nov. 6.
Impact of MTX + TNFi Treatment on Cardiovascular Risk in RA
• Design: RA inception cohort using electronic health records
• Subjects: 1718 RA patients without history of CVD
• Primary outcome: Incident CVD, including any o the following: Coronary artery disease (CAD) Cardiac or arterial revasc. procedure Stroke / TIA Abdominal aortic aneurysm Peripheral artery disease
Bozaite-Gluosniene R. Presented at ACR 2011; Presentation #719.
Impact of MTX + TNFi Treatment on Cardiovascular Risk in RA: Co-variates
Category Co-variates
Demographics Age, gender, ethnicity
ComorbiditiesBMI (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 byCumulative TNF-α Inhibitor Use
Never ≤ 17 mo >17 mo
No. of patients 1147 286 285
No. of CVD events 102 16 9
HR* (95% CI)
1.04 (0.57-1.88)
0.31 (0.15-0.63)
* Adjusted for propensity score, age, gender, race, propensity score, body mass index, history of hypertension, hyperlipidemia and diabetes, ESR, CRP, RF and anti CCP antibodies and use of NSAIDs, glucocorticoids, HCQ and MTX
Bozaite-Gluosniene R. Presented at ACR 2011; Presentation #719.
Risk of Developing CVD byCumulative Methotrexate Use
Never ≤ 22 mo > 22 mo
No. of patients 652 532 534
No. of CVD events 70 35 22
HR* (95% CI)
1.15 (0.71-1.86)
0.28 (0.16-0.49)
* Adjusted for age, gender, race, propensity score, body mass index, history of hypertension, hyperlipidemia and diabetes, ESR, CRP, RF and anti-CCP antibodies, and use of glucocorticoids, HCQ, TNF-α inhibitors, and NSAIDs
Bozaite-Gluosniene R. Presented at ACR 2011; Presentation #719.
Impact of MTX + TNFi Treatment on Cardiovascular Risk in RA: Conclusions
• In this inception RA cohort, use of MTX >22 months was independently associated with a 72% reduction in risk of incident CVD
• Use of TNF-α inhibitors >17 months was independently associated with a 69% reduction in risk of incident CVD
• The findings are biologically plausible, given the role of inflammation in atherosclerosis and the potent anti-inflammatory effects of these medications that may take several months to manifest their effect
• These findings suggest that these medications are protective against CVD in a group of patients at high risk for CVD
Bozaite-Gluosniene R. Presented at ACR 2011; Presentation #719.
113
Late-breaking Abstracts
Highlights of an ACR Concurrent Abstract Session, Tuesday,
November 8Summarized by Dr. Janet Pope
List of Presentations in this Section
Speaker / primary author Title Abstract #
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-to-Severe Rheumatoid Arthritis: Results of a Phase 2, Randomized, Double-Blind, Placebo-Controlled, International Study
L2
Tak PPSafety and Efficacy of Oral Chemokine Receptor 1 Antagonist CCX354-C in a Phase 2 Rheumatoid Arthritis Study
L11
114Concurrent abstract session:Late-breaking abstracts. ACR 2011; Tues., Nov. 8.
List of Presentations in this Section (cont'd)
Speaker / primary author Title Abstract #
Becker LM
BCX4208 Combined with Allopurinol Increases Response Rates in Patients with Gout Who Fail to Reach Goal Range Serum Urate on Allopurinol Alone: A Randomized, Double-Blind, Placebo-Controlled Trial
L10
Ko VWIs Centre-Based Rehabilitation Superior to Home-Based Rehabilitation After Knee Replacement? A Single-Blind, Randomised Controlled Trial
L6
Brown JP
Six Years of Denosumab Treatment in Postmenopausal Women with Osteoporosis: Results From the First Three Years of the FREEDOM Extension
L8
115Concurrent abstract session:Late-breaking abstracts. ACR 2011; Tues., Nov. 8.
116
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.
117
Response
Mavrilimumab for RA: Time to Onset of DAS28 Response & Remission
Response Remission
Burmester GR. Presented at ACR 2011; Presentation #L7.
Remission
Mavrilimumab for RA:ACR20, 50 & 70 at Day 85
118Burmester GR. Presented at ACR 2011; Presentation #L7.
Mavrilimumab for RA:ACR50 and 70 By Visit
ACR50
ACR50
ACR70
ACR70
119Burmester GR. Presented at ACR 2011; Presentation #L7.
120
Mavrilimumab for RA: Conclusionsfrom a Phase 2 Study
• Mavrilimumab was associated with: A rapid (within 2 wks) and significant clinical
effect compared with placebo A safety profile over the first 3 months of dosing
that had no reported serious and opportunistic infections, hypersensitivity reactions, anaphylaxis, clinically meaningful adverse events, or laboratory abnormalities up to the highest dose tested
• The results from this study suggest that suppressing macrophage activity by targeting GM-CSFRα may be a novel approach in the treatment of RA and supports future clinical studies
Burmester GR. Presented at ACR 2011; Presentation #L7.
Sarilumab for Moderate-to-Severe RA:Phase 2 Study
• Sarilumab = fully human monoclonal antibody directed against IL-6Rα
• Objective: To evaluate the efficacy and safety of 5 dose regimens of subcutaneous sarilumab vs. placebo (both with MTX) in RA
• Subjects: 306 adults with active, moderate-to-severe RA with inadequate response to MTX
• Method: 12-week double-blind trial Subjects randomized to sarilumab 100 mg q2w,
150 mg q2w, 100 mg qw, 200 mg q2w, 150 mg qw, or placebo
Primary endpoint: % achieving ACR20 at Week 12
Genovese MC, et al. Presented at ACR 2011; Presentation #L2.
Sarilumab for Moderate-to-Severe RA:Phase 2 Study
Genovese MC, et al. Presented at ACR 2011; Presentation #L2.
Placebo 100 mg q2w
150 mg q2w
100 mg qw
200 mg q2w
150 mg qw
0
10
20
30
40
50
60
70
80
ACR20 ACR50 ACR70
% a
chie
vin
g A
CR
res
po
nse
s
Sarilumab dose
Oral Chemokine Receptor 1 Antagonist CCX354-C in RA: Phase 2 Study
• Objective: To evaluate safety, tolerability and efficacy of CCX354-C in subjects with RA with inadequate response to MTX
• Subjects: 160 adult subjects with RA, on stable dose of MTX ≥ 8 SJC, 8 TJC (based on 66/68 joint count) CRP > 5 mg/L
• Methods: Randomized, 12-week double-blind, placebo-controlled, parallel group Stratification based on previous biologics use, and current
corticosteroid use Randomized to placebo, CCX354-C 100 mg bid or 200 mg qd Efficacy measures: ACR, DAS28, CRP, ESR, bone turnover
markers
Tak PP. Presented at ACR 2011; Presentation #L11.
Oral Chemokine Receptor 1 Antagonist CCX354-C in RA: Phase 2 Study
ACR20 at Week 12 Placebo 100 mg
BID 200 mg
QD P-value
ITT, Day 1 Eligible Subjects
30% 44% 56% 0.014
ITT, Including Day 1 Ineligible Subjects
39% 43% 52% 0.17
Biologic-naïve 35% 42% 57% 0.059
Day 1 Eligible, Biologics-naïve
27% 42% 62% 0.002
Tak PP. Presented at ACR 2011; Presentation #L11.
BCX4208 Combined with Allopurinol in Gout
• BCX4208 = Purine nucleoside phosphorylase (PNP) inhibitor
• Objective: To evaluate BCX4208 therapy added on to allopurinol 300mg in allopurinol inadequate responders
• Subjects: 279 patients with gout Baseline sUA ≥ 6.0 mg/dL after 2 weeks on
300mg of allopurinol • Methods:
Primary endpoint: % patients with sUA < 6mg/dL at week 12
Long-term extension is ongoing Becker LM. Presented at ACR 2011; Presentation #L10.
BCX4208 Combined with Allopurinol in Gout: Primary Efficacy Results
Placebo 5 mg 10 mg 20 mg 40 mg0%
10%
20%
30%
40%
50%
60%
18%
45%*
33%
39%*
49%†
% a
chie
vin
g
sUA
< 6
mg
/dL
at
wee
k 12
*p<0.05; †p<0.001 Becker LM. Presented at ACR 2011; Presentation #L10.
BCX4208 dose
Centre-based vs. Home-based Rehabilitation After Knee Replacement: Single-Blind RCT
• Subjects: 249 patients requiring supervised physical therapy after total knee replacement
• Methods: Two-weeks post-surgery, subjects
randomized to:– 12 sessions of 1-to-1 therapy– 12 sessions of group based therapy– Home exercises supplemented with two 1-
to-1 sessions and a telephone follow-up • Results: Supervised outpatient sessions are
not superior to a monitored home programme after TKR
Ko VW, et al. Presented at ACR 2011; Poster #L6.
Denosumab for Postmenopausal Women with Osteoporosis: 6-year Results from the FREEDOM Extension
• Objectives: To describe the effects of up to 6 years of denosumab treatment on: Bone turnover and bone density Safety: incidence of new vertebral and
nonvertebral fractures, incidence of adverse events
• Subjects: 2,207 patients crossed over from placebo to
denosumab after double-blind period 2,343 patients treated with long-term
denosumab from the start of the trial
Brown JP. Presented at ACR 2011; Presentation #L8.
Denosumab for Postmenopausal Women with Osteoporosis: % Change in BMD at the Lumbar Spine and Total Hip
*p < 0.05 vs FREEDOM baseline; †p < 0.0001 vs FREEDOM and extension baseline. Brown JP. Presented at ACR 2011; Presentation #L8.
Denosumab for Postmenopausal Women with Osteoporosis: Conclusions from the FREEDOM Extension Study
*p < 0.05 vs FREEDOM baseline; †p < 0.0001 vs FREEDOM and extension baseline. Brown JP. Presented at ACR 2011; Presentation #L8.
• Denosumab treatment for 6 years (long-term group): Maintained the reduction in bone turnover Continued to significantly increase BMD year
to year Was associated with low incidences of new
vertebral and nonvertebral fractures Remained well tolerated
• Denosumab treatment for 3 years (cross-over group) largely reproduced the observations in the original FREEDOM denosumab group
131
Spondylarthropathies:Recent Insights
Highlights of an ACR Clinical Symposium,
Tuesday, November 8Summarized by Dr. Majed Khraishi
List of Presentations in this Section
Speaker / primary author
Title Abstract #
Maksymowych WPTNF Inhibition and Structural Progression in Ankylosing Spondylitis
NA
Kingsley GHIs Methotrexate a Disease Modifying Agent in Psoriatic Arthritis?
NA
Khraishi MAnalysis of Radiographic Changes in Patients with Early Psoriatic Arthritis
1548
132Clinical Symposium:Spondylarthropathies: Recent Insights. ACR 2011; Tues., Nov. 8.
Hypothesis: Inflammation and AnkylosisAre 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: Pathogenesisof New Bone in Ankylosing Spondylitis
Maksymowych WP. Clinical Symposium " Spondylarthropathies: Recent Insights".Presented at ACR 2011.
Evidence for Methotrexate in PsA:Observations from the NOR-DMARD Registry
Lie E, et al. Ann Rheum Dis. 2010; 69(4):671-6.Cited by Kingsley GH. Clinical Symposium " Spondylarthropathies: Recent Insights".Presented at ACR 2011.
• After 6 months MTX PsA and RA patients show improvements in most
disease activity measures and patient reported outcomes
In adjusted analysis less improvement with PsA, but changes in same range as RA
EULAR good/moderate responses were achieved by 24%/57% PsA and 33%/70% RA
• At 2 years Retention rates on MTX were 65% PsA and 66% RA Only minor differences in reasons for discontinuation
Evidence for Methotrexate in PsA:MTX in Psoriatic Arthritis (MIPA) Trial
• Hypothesis: MTX improves disease activity and function in psoriatic arthritis
• Design: 6-month RCT comparing MTX with placebo
• Inclusion criteria: Synovitis in ≥ 1 joint, psoriasis skin/nails
• Exclusion criteria: Other arthropathies, recent steroids/DMARDs, contra-indications to MTX
• Interventions: MTX (target 15mg/wk) or placebo
• Primary outcome: Psoriatic Arthritis Response Criteria
• Secondary outcomes: Patient & assessor global assessments, HAQ & Pain, TJC, SJC, ESR, CRP, composite measures
Kingsley GH. Clinical Symposium " Spondylarthropathies: Recent Insights".Presented at ACR 2011.
Evidence for Methotrexate in PsA:MTX in Psoriatic Arthritis (MIPA) Trial
Kingsley GH. Clinical Symposium " Spondylarthropathies: Recent Insights".Presented at ACR 2011.
MTX Placebo
3 months 6 months
% o
f p
atie
nts
% o
f p
atie
nts
Evidence for Methotrexate in PsA:MTX in Psoriatic Arthritis (MIPA) Trial
Kingsley GH. Clinical Symposium " Spondylarthropathies: Recent Insights".Presented at ACR 2011.
MTX Placebo
Evidence for Methotrexate in PsA:Conclusions from the MIPA Trial
Kingsley GH. Clinical Symposium " Spondylarthropathies: Recent Insights".Presented at ACR 2011.
• MTX In PsA: Improves symptoms Has no effect on joint counts or acute phase
response Is a “symptom modifying agent” and not a
“DMARD”
Radiographic Changes in Patientswith 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
140Khraishi M, et al. Presented at ACR 2011; Poster #1548.
141
Impact of Body Weight in Rheumatic Disease
Selected Highlights from Various ACR Sessions
Summarized by Dr. Robert Offer
List of Presentations in this Section
Speaker / primary author Title Abstract #
Smolen JSImpact 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
142Various ACR sessions. ACR 2011; Nov. 6-8.
List of Presentations in this Section
Speaker / Primary author
Title Abstract #
Wolfe FThe Effect of Body Mass Index On the Outcomes of Rheumatoid Arthritis
2586
Greenberg JDEffect 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
143Various ACR sessions. ACR 2011; Nov. 6-8.
Does BMI Affect OutcomesWith Biologics in RA?
Smolen JS, et al. Presented at ACR 2011; Poster #410.
Probability of DAS28 Remission*Response to ETN-MTX by BMI category at Week 36 in Subjects w/ Moderate RA
Variable
% of subjectsp
valueBMI<25 kg/m2
BMI 25 -<30 kg/m2
BMI≥30 kg/m2
DAS28Remission (<2.6) 70.8 68.1 56.7 0.01
LDAS (<3.2) 87.5 86.5 79.5 0.05
CDAIRemission (≤2.8) 29.5 28.0 17.3 0.02
LDA (<10) 85.4 81.2 78.7 0.06
SDAIRemission (≤3.3) 27.7 26.7 16.0 0.02
LDA (<11) 86.8 83.8 81.6 0.13
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
BMI
Proportion Achieving DAS≤2.4
x 6 months
<25 84%
25-30 68%
>30 64%
Heimans L, et al. Presented at ACR 2011; Poster #416.
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 RAby 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)*
*Statistically significant vs. normal weightWolfe F. Presented at ACR 2011; Presentation #2586.
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.
Predictors of Efficacy ofTNF-inhibitors in Psoriatic Arthritis
Hazard Ratio 95% CI p-value
Fixed dosing (vs. weight-based) 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.
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)
• 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.
Total group:% obese
Men: % obese
Women: % obese
DEXA 58% 80% 44%
BMI 27% 29% 26%
152
Impact of Environmental Healthon Autoimmunity
Highlights of an ACR Clinical Symposium,
Sunday, November 6Summarized by Dr. Hector Arbillaga
List of Presentations in this Section
Speaker Title
Miller FThe Environment and Autoimmune Diseases – Where we stand in 2011
James JAThe Role of Gene X Environment Interactions in Autoimmunity
Cooper GSSmoking and Silica Exposure-Models for Exploring Environmental Triggers of Disease
153Clinical Symposium:Impact of Environmental Health on Autoimmunity. ACR 2011; Sun., Nov. 6.
Chemical Factors Associated with Autoimmune Diseases
• Crystalline silica exposure contributes to development of RA, SScl, SLE and anti-neutrophil 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.
158
The Role of Gene X EnvironmentInteractions 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.
159
The Role of Gene X EnvironmentInteractions 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.
Smoking and Rheumatoid Arthritis:Influence on Pathogenesis
160
Cooper GS. Clinical Symposium "Impact of Environmental Health on Autoimmunity".Presented at ACR 2011.
SmokingGeneration of modified peptides
(citrullination) in lungs
Activation of adaptive immune response- Antigen presentation (DRB1-SE binding)
- T-cell activation (PTPN22)
"Priming" for systemic immunity
161
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.
162
Orthopedics, Low Back Pain, and Rehabilitation
Highlights of an ACR Poster Session, Monday, November 7
Summarized by Dr. Anthony Russell
List of Presentations in this Session
Primary author TitleAbstract #
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 JA Phase 3 Placebo- and Oxycodone-Controlled 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
163Poster session:Orthopedics, Low Back Pain, and Rehabilitation. ACR 2011; Mon., Nov. 7.
164
Duloxetine for Osteoarthritis inOlder 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.
Duloxetine for Osteoarthritis inOlder Adults: Changes in Daily Pain Diaries
165
*p < 0.05; †p < 0.01; ‡p < 0.001Micca JL, et al. Presented at ACR 2011; Poster #1094.
(< 65 years) (≥ 65 years)
166
Phase 3 Study of Tanezumabfor 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; up-titrated & 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.
Phase 3 Study of Tanezumab for Adultswith Osteoarthritis: Week 8 Results
167Fidelholtz J, et al. Presented at ACR 2011; Poster #1095.
Tanezumab Added to Diclofenacfor 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, placebo-controlled 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
168Feist E, et al. Presented at ACR 2011; Poster #1096.
Tanezumab Added to Diclofenacfor Hip or Knee OA
PBO: Placebo; DSR: Diclofenac sustained release; TZB: tanezumabFeist E, et al. Presented at ACR 2011; Poster #1096.
170
Osteoporosis and Metabolic Bone Disease: Clinical Aspects
and Pathogenesis
Highlights of an ACR Concurrent Abstract Session,
Monday, November 7Summarized by Dr. Philip Baer
List of Presentations in this Section
Speaker Title Abstract #
Amin SFracture Risk Is Increased in Young Women with Rheumatoid Arthritis
1632
Schoushoe JT
Does Identification of Prevalent Vertebral Fracture on Densitometric Vertebral Fracture Assessment (VFA) in Clinical Practice Influence Physician Prescribing Behavior?
1634
171Concurrent abstract session: Osteoporosis and Metabolic Bone Disease:Clinical Aspects and Pathogenesis. ACR 2011; Mon., Nov. 7.
Fracture Risk By Age and Sex in RA
Hazard ratio (95% CI)
All < 50 years ≥ 50 years
Women
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)
Men
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)
*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 WithBaseline 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 Fractureson 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 Useor 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 Fractureson 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.
184
Systemic Sclerosis (SSc), Fibrosing Syndromes and
Raynaud's—Clinical Aspectsand Therapeutics
Highlights of ACR Concurrent Abstract and Poster Sessions,
Monday, November 7Summarized by Drs. Clode Lessard
& Janet Pope
List of Presentations in this Section
Speaker Title Abstract #
Johnson SR
Effect of Warfarin On Survival In Scleroderma-Associated and Idiopathic Pulmonary Arterial Hypertension. A Bayesian Approach to Evaluating Treatment In Uncommon Disease
2481
Schreiber BEDiffusion of Carbon Monoxide Predicts Survival in Systemic Sclerosis Patients with Pulmonary Hypertension and Interstitial Lung Disease
2482
Seibold JRDigital Ischemic Ulcers in Scleroderma Treated with Oral Treprostinil Diethanolamine: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study
2483
Rodriguez-Reyna TS
Microvascular Damage and Cardiac Fibrosis Detected by Heart MRI are a Hallmark of Systemic Sclerosis Heart Involvement
2484
185Concurrent abstract and poster sessions: Systemic Sclerosis (SSc), FibrosingSyndromes and Raynaud's—Clinical Aspects and Therapeutics. ACR 2011; Mon., Nov. 7.
List of Presentations in this Section, cont'd
Speaker / Primary author Title Abstract #
Domsic RTDevelopment 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
186Concurrent abstract and poster sessions: Systemic Sclerosis (SSc), FibrosingSyndromes and Raynaud's—Clinical Aspects and Therapeutics. ACR 2011; Mon., Nov. 7.
List of Presentations in this Section, cont'd
Speaker Title Abstract #
Jordan SEffects 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
187Concurrent abstract and poster sessions: Systemic Sclerosis (SSc), FibrosingSyndromes and Raynaud's—Clinical Aspects and Therapeutics. ACR 2011; Mon., Nov. 7.
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 0.017
Schreiber BE. Presented at ACR 2011; Presentation #2484.
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
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.
Prevalence of cardiac fibrosis
Total Diffuse Limited p
Late enhancement on MRI 28 (45%) 17 (58.6%) 11 (33.3%) 0.04
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%
Domsic RT. Presented at ACR 2011; Presentation #2485.
Variables predicting mortality
Age at first visit Severity of muscle involvement
Rapid progression of skin involvement Severity of cardiac involvement
Severity of GI involvement Anemia
Is Race Related to Mortality Risk in Scleroderma?
• Design: Chart review from 1990 to 2009 of scleroderma patients seen at the scleroderma clinic in Baltimore (n=2217)
Gelber AC. Presented at ACR 2011; Presentation #2486.
Model Relative Risk,
Black compared toWhite Patients
95%CI
Unadjusted 1.3 1.1 – 1.5
Age, duration-adjusted 1.6 1.3 – 1.9
Age, duration, gender, subtype-adjusted
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
Abatacept for Diffuse Cutaneous Systemic Sclerosis: Pilot Study
Abatacept (n=7)
Placebo(n=3)
p value
Change in HAQ-DI -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
Change in Physician Global -11.9 (18.1) -17.3 (23.2) 0.048
Change in Patient Global -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
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 Rituximabin 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.
NB: Not an RCT, no control group.
Ambrisentan for Digital Ulcers in Patients with Systemic Sclerosis: Pilot Study
Chung L, et al. Presented at ACR 2011; Poster #668.
Mean # of Total DU per Patient
199
Complicated Raynaud's Phenomenon
Highlights of an ACR Clinical Symposium, Sunday, November 6
Summarized by Dr. Philip Baer
List of Presentations in this Section
Speaker Title
Wigley F Complicated Raynaud’s Phenomenon
200Clinical SymposiumComplicated Raynaud's Phenomenon. ACR 2011; Sun., Nov. 6.
What is needed to make a Diagnosis ofRaynaud’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 PhenomenonInvolves 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.
210
Vasculitis
Highlights of ACR Poster Sessions, November 7 & 8
Summarized by Drs. Robert Offer and Peter Panopalis
List of Presentations in this Section
Primary author Title Abstract #
Schmidt JStatin 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 MGTocilizumab: 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
211Poster sessions. Vasculitis. ACR 2011; Nov. 7 & 8.
List of Presentations in this Section
Primary Author Title Abstract #
Pagnoux C
Are Patients with ANCA-Associated Vasculitis Entered In Clinical Trials Representative of Patients Followed In Observational Cohorts?
2368
Tomasson GOptimal Definition for the Duration of Sustained Remission in ANCA-Associated Vasculitis
2369
Davids ML
Mental Health As a Predictor of Disease Flare in Granulomatosis with Polyangiitis (Wegener's Granulomatosis)
2371
212Poster sessions. Vasculitis. ACR 2011; Nov. 7 & 8.
Effect of Statin Use onRisk 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.
Statins Reduce the Risk of Giant Cell Arteritis
GCA Controls0%
20%
40%
60%
80%
100%
14.1%
33.3%
% w
ith
sta
tin
us
e a
t b
as
eli
ne
• Patients with GCA were less often users of statins compared to controls
• 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)
Schmidt J, et al. Presented at ACR 2011; Poster #1512.
No Steroid-sparing Effect forAdalimumab in Giant Cell Arteritis
Mariette X, et al. Presented at ACR 2011; Poster #1508. ACR 2011
Mea
n c
han
ge
in p
red
nis
on
e d
ose
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
Catanoso MG, et al. Presented at ACR 2011; Poster #1505.
ESR (mm/h) CRP (mg/dL) ITAS KERR
BeforeTCZ
After TCZ
BeforeTCZ
After TCZ
BeforeTCZ
After TCZ
BeforeTCZ
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
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 ANCA-Associated Vasculitis in Observational Cohorts & Clinical Trials
Variable 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
Mean creatinine (µmol/l ± SD) 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
Death 14 (3.3) 49 (22.3) <0.001
Relapse 256 (60.5) 101 (45.9) 0.01
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 regimensTomasson 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.
221
Fibromyalgia and Soft Tissue Disorders
Highlights of an ACR Concurrent Abstract Session, Monday,
November 7Summarized by Dr. Robert Offer
List of Presentations in this Session
Speaker Title Abstract #
Ste-Marie PAContinued Opioid Use in Fibromyalgia Is Associated with Negative Health Related Outcomes
1605
Wolfe FAn 11-Year Longitudinal Study of Pharmacologic Therapy in Fibromyalgia
1610
222Concurrent abstract session. Fibromyalgia and Soft Tissue Disorders. ACR 2011; Mon., Nov. 7.
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
ALLn=131
Opioid usersn=43
Non-usersn=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 q6moWolfe F, et al. Presented at ACR 2011; Presentation #1610.
11-year Longitudinal Study of Pharmacotherapy for Fibromyalgia: Centrally Acting Agents
N=2870, assessed q6moWolfe F, et al. Presented at ACR 2011; Presentation #1610.
11-year Longitudinal Study of Pharmacotherapy for Fibromyalgia: Centrally Acting Agents
N=2870, assessed q6moWolfe F, et al. Presented at ACR 2011; Presentation #1610.
228
Autoimmune Myopathies
Highlights of Various ACR Sessions, November 6-9
Summarized by Dr. Yves Troyanov
List of Presentations in this Section
Speaker / Primary Author Title Abstract #
Christopher-Stine 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
229Various ACR 2011 Sessions; November 6-9.
List of Presentations in this Section
Speaker / Primary Author Title Abstract #
Ceribelli AAnti-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
Agudelo-Hernandez 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
230Various ACR 2011 Sessions; November 6-9.
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 theInflammatory 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 theInflammatory 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 non-septal linear or plate-like opacities
Fiorentino D. Clinical Symposium " Emerging Concepts in theInflammatory 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 theInflammatory 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
p value
Male 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% 0.05
Elevated CPK at last visit 0% 25%
Ceribelli A, et al. Presented at ACR 2011; Poster #231.
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 Result
Inflammation only 0
Necrosis only 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.