1 ACR 2011 Medical Passport Highlights of ACR 2011 Chicago, IL November 2011

1

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


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


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)


MTX + Etanercept or Placebo in RA:Conclusions from the EMPIRE Study


• Rapid clinical responses were demonstrated with MTX + ETN combination therapy

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

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

• High response rates to MTX still need to be explained

13

Rheumatoid Arthritis: Clinical Aspects

Highlights of ACR Poster and Concurrent Abstract Sessions,

Sunday November 6Summarized by Drs. Robert Offer and

Peter Panopalis


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)


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



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.

28

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

MetrologyHighlights of an ACR Poster

Session, Tuesday, November 8Summarized by Dr. Robert Offer



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


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


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


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.



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




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




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


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


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


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


Abatacept in Real-World Practice:Overall Treatment Durability


Abatacept in Real-World Practice:Treatment Durability by Prior Treatment


Abatacept in Real-World Practice:Achievement of Clinically Important HAQ Change


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


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.


51

RAPID3 component scores at baseline


52

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


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


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


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


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.


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.


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



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


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


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


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


• 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


Ultrasound for Prediction of Ongoing Joint Destruction: Patient Disposition


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


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


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?


106

Discovery 2011

Highlights of an ACR Plenary Session, Sunday, November 6

Summarized by Dr. Robert Offer

Presentation in this Section


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


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


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


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


113

Late-breaking Abstracts

Highlights of an ACR Concurrent Abstract Session, Tuesday,

November 8Summarized by Dr. Janet Pope



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.



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


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


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


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.



MTX Placebo

3 months 6 months

% o

f p

atie

nts

% o

f p

atie

nts



MTX Placebo

Evidence for Methotrexate in PsA:Conclusions from the MIPA Trial


• MTX In PsA: Improves symptoms Has no effect on joint counts or acute phase

response Is a “symptom modifying agent” and not a

“DMARD”

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



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.


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


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


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


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


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



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


Fracture Risk in RA: Women With Baseline Age < 50 Years


Fracture Risk in RA: Women < 50 Years & Follow-up Limited to Age 50 Years


Fracture Risk in RA: All Men


Fracture Risk in RA: Men WithBaseline Age < 50 Years


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


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%


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)


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%


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


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



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


List of Presentations in this Section, cont'd


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


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


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


Primary Raynaud’s PhenomenonInvolves All Digits Symmetrically


In Raynaud's, the Thumb is Less Often Involved But Not Spared


In Raynaud's, Pallor Beyond the MCP Joints is Worrisome


Treatment Considerations for Raynaud's


Treatment Considerations for Raynaud's, Cont'd


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


210

Vasculitis

Highlights of ACR Poster Sessions, November 7 & 8

Summarized by Drs. Robert Offer and Peter Panopalis


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.


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%

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sta

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• 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

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han

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in p

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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


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


11-year Longitudinal Study of Pharmacotherapy for Fibromyalgia: Centrally Acting Agents


228

Autoimmune Myopathies

Highlights of Various ACR Sessions, November 6-9

Summarized by Dr. Yves Troyanov


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.


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


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


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.

Documents

1 ACR 2011 Medical Passport Highlights of ACR 2011 Chicago, IL November 2011