1 EULAR 2011 Medical Passport Highlights of EULAR 2011 London, United Kingdom June 2011

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EULAR 2011 Medical PassportEULAR 2011 Medical Passport

Highlights of EULAR 2011Highlights of EULAR 2011

London, United KingdomLondon, United Kingdom

June 2011June 2011

Medical Passport Program-EULAR 2011 2

FacultyFaculty

Lillian Barra, MDLillian Barra, MD

George Ecker, MD George Ecker, MD

Isabelle Fortin, MDIsabelle Fortin, MD

Jacob Karsh, MDJacob Karsh, MD

Nader Khalidi, MDNader Khalidi, MD

Majed Khraishi, MDMajed Khraishi, MD

Liam Martin, MDLiam Martin, MD

Wojciech Olszynski, MDWojciech Olszynski, MD

Janet Pope, MDJanet Pope, MD

Anthony Russell, MDAnthony Russell, MD

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DisclosureDisclosure

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

Gums, joints and inflammation Lillian Barra, MD

Cytokines with a double edge sword Lillian Barra, MD

From bench to bedside: New insights into pathogenesis and pathophysiology of AS

George Ecker, MD

Clinical aspects of SpA – What is new?: Abstract session

George Ecker, MD

Osteoporosis: Selected posters George Ecker, MD

RA - A life without biologics: Abstract session

Isabelle Fortin, MD

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OutlineOutline

RA: Nothing is working! What to do? Isabelle Fortin, MD

RA: Selected posters Isabelle Fortin, MD

Bone and crystal diseases Jacob Karsh, MD

Inflammasomes as sentinelsand enemies from within

Jacob Karsh, MD

RA & advanced therapeutics: selected posters

Jacob Karsh, MD

Vasculitis: abstract session Nader Khalidi, MD

Last but not least: The orphans Nader Khalidi, MD

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OutlineOutline

Pathogenesis of ANCA-associated vasculitis

Nader Khalidi, MD

Psychiatric disease in rheumatology practice

Liam Martin, MD

Tight control: theory and practice Liam Martin, MD

The earliest phase of RA Liam Martin, MD

Fibromyalgia: selected posters Liam Martin, MD

Genomics, genetics, epigenetics Wojciech Olszynski, MD

Epigenetic regulation of inflammation Wojciech Olszynski, MD

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OutlineOutline

Osteoporosis: Abstract session Wojciech Olszynski, MD

Too much immunoglobulin - diseases relevant for the rheumatologist

Anthony Russell, MD

Myositis and myopathies Anthony Russell, MD

Update in RA therapeutics: targeting intracellular signalling

Anthony Russell, MD

RA – Non-TNF biologics: Abstract session & selected posters

Janet Pope, MD

Late-breaking abstracts Majed Khraishi, MD

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OutlineOutline

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Gums, joints and inflammationGums, joints and inflammation

Highlights of the EULAR Basic Highlights of the EULAR Basic and Translational Science Session and Translational Science Session

held Wednesday, May 25held Wednesday, May 25Summarized by Dr. Summarized by Dr. Lillian BarraLillian Barra

List of Presentations in this SessionList of Presentations in this Session

Speaker TitleAbstract # (if applicable)

De Pablo, P The epidemiology of RA and tooth loss NA

Venables, PThe biology of citrullination in periodontal disease and RA

NA

Bartold, MThe relationship betweenperiodontitis and RA

SP0026

Potemper, JThe corruption of innate immunityby bacterial proteases

SP0027

9Basic & Translational Science session:Gums, Joints & Inflammation. EULAR 2011; Wed., May 25.

Periodontitis: BackgroundPeriodontitis: Background

• Caused by bacterial infection.Caused by bacterial infection.

• Causative agent is Causative agent is P. gingivalis P. gingivalis

• Leads to inflammatory response in the gum Leads to inflammatory response in the gum endotheliumendothelium

• Endothelium ulcerates and the cumulative Endothelium ulcerates and the cumulative surface area of involved tissue is significant surface area of involved tissue is significant enough to cause systemic inflammation enough to cause systemic inflammation

Basic & Translational Science session:Gums, Joints & Inflammation. EULAR 2011; Wed., May 25.

Periodontitis and RAPeriodontitis and RA

• Both are systemic inflammatory diseases that Both are systemic inflammatory diseases that have similar:have similar:

Inflammatory mediatorsInflammatory mediators

Erosive bone diseaseErosive bone disease

Associations Associations

– SmokingSmoking

– HLA-DR4HLA-DR4

– CADCAD


Are Patients with RA At RiskAre Patients with RA At Riskof Periodontitis and Vice Versa?of Periodontitis and Vice Versa?

• De Pablo et al, J Rheum 2008:De Pablo et al, J Rheum 2008:

N = 4461N = 4461

OR = 4.13 (PD in RA patients)OR = 4.13 (PD in RA patients)

OR = 1.5 (RA in PD patients)OR = 1.5 (RA in PD patients)

• De Smit et al [EULAR 2011: Abstract THU0289]De Smit et al [EULAR 2011: Abstract THU0289]

N = 98 RA patients, 51% with PDN = 98 RA patients, 51% with PD

PD had higher DAS, increased smoking, PD had higher DAS, increased smoking, increased ACPAincreased ACPA


Are Patients with RA At RiskAre Patients with RA At Riskof Peridontitis and Vice Versa?of Peridontitis and Vice Versa?

• Nurse’s Health Study (Arkema et al, J Rheum Nurse’s Health Study (Arkema et al, J Rheum 2010):2010):

N = 81132N = 81132

No association between PD and RANo association between PD and RA

PD associated with smokingPD associated with smoking

• Why the difference between studies????Why the difference between studies????

Classification of diseaseClassification of disease

Patient populationPatient population

ConfoundersConfounders


Does PD cause RA and vice versa?Does PD cause RA and vice versa?The Role of CitrullineThe Role of Citrulline

• Anti-Citrullinated Protein Antibodies (ACPA) Anti-Citrullinated Protein Antibodies (ACPA) appear to be pathogenicappear to be pathogenic

Mice immunized with citrullinated enolase Mice immunized with citrullinated enolase produce anti-citrullinated enolase antibodies produce anti-citrullinated enolase antibodies and develop arthritis and develop arthritis

Other mouse models support thisOther mouse models support this

Citrullinated proteins and ACPA complexes Citrullinated proteins and ACPA complexes are found in the joints of RA patientsare found in the joints of RA patients

• Citrulline is produced by an enzyme called Citrulline is produced by an enzyme called Peptidyl Arginine Deiminase (PAD)Peptidyl Arginine Deiminase (PAD)


Peptidyl Arginine Deiminase (PAD): Peptidyl Arginine Deiminase (PAD): Therapeutic Target?Therapeutic Target?

• PADs thought to be important for RA include:PADs thought to be important for RA include:

Human PAD2, human PAD4, Human PAD2, human PAD4, P. gingivalisP. gingivalis PAD PAD (PPAD)(PPAD)

– PPAD can citrullinate both bacterial and human PPAD can citrullinate both bacterial and human proteins which can lead to autoimmunityproteins which can lead to autoimmunity

– 2-Chloracetamidine can inhibit PPAD but is too 2-Chloracetamidine can inhibit PPAD but is too toxic for clinical usetoxic for clinical use

– Other inhibitory molecules are being Other inhibitory molecules are being developed that may have therapeutic benefitdeveloped that may have therapeutic benefit

Which PAD to inhibit?Which PAD to inhibit?

What is physiologic role of citrullination?What is physiologic role of citrullination?


Importance of Importance of P. gingivalisP. gingivalis::Observations from Mouse ModelsObservations from Mouse Models

• Mice were infected with P. gingivalis and CIA Mice were infected with P. gingivalis and CIA was induced in these mice:was induced in these mice:

1.1. CIA + CIA + P. gingivalis P. gingivalis have more severe arthritis have more severe arthritis than CIA alone and more severe PD than P. than CIA alone and more severe PD than P. gingivalis alonegingivalis alone

2.2. These mice had citrullinated proteins These mice had citrullinated proteins present in the gumspresent in the gums

3.3. CIA mice not injected with CIA mice not injected with P. gingivalis P. gingivalis also also had PD whereas WT mice did nothad PD whereas WT mice did not


Importance of Importance of P. gingivalisP. gingivalis::Observations From Mouse Models (cont'd)Observations From Mouse Models (cont'd)

• Mice preinjected with Mice preinjected with anyany infectious organism infectious organism will have similar resultswill have similar results

• Therefore:Therefore:

Any inflammatory process in pre-arthritis Any inflammatory process in pre-arthritis stage worsens arthritisstage worsens arthritis

Other factors are clearly at play – multiple hit Other factors are clearly at play – multiple hit hypothesishypothesis

IA appears to predispose to PDIA appears to predispose to PD


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Cytokines with aCytokines with aDouble-edged SwordDouble-edged Sword


held Wednesday, May 25held Wednesday, May 25Summarized by Dr. Summarized by Dr. Lillian BarraLillian Barra



Brusewitz, M

The problems I have experienced from my RA and how health professionals have intervened to assist me in resolving them

NA

Opava, CReflections on the limitations of traditional measures in clinical studies

NA

Oesch, P

The influence of language and literacy on the use of patient reported outcomes and consequences for health care research

OP0099

19Basic & Translational Science session:Cytokines with a Double Edged Sword. EULAR 2011; Wed., May 25.

IL-22: Pathogenic vs. ProtectiveIL-22: Pathogenic vs. Protective

• Elevated in Psoriasis, IBD, RAElevated in Psoriasis, IBD, RA

• Produced by Th17 cells and NK cellsProduced by Th17 cells and NK cells

• Binds to IL-22R, which are found on epithelial Binds to IL-22R, which are found on epithelial cellscells

Basic & Translational Science session:Cytokines with a Double Edged Sword. EULAR 2011; Wed., May 25.

Evidence for IL-22 PathogenesisEvidence for IL-22 Pathogenesis

• Experiments done in a mouse model of IBDExperiments done in a mouse model of IBD

1.1. Mice deficient in IL-22 were producedMice deficient in IL-22 were produced

2.2. Acute IBD-like disease induced in these miceAcute IBD-like disease induced in these mice

• Results:Results:

Mice had more severe epithelial ulceration Mice had more severe epithelial ulceration

• Conclusions:Conclusions:

IL-22 has an important role in epithelial IL-22 has an important role in epithelial repair in acute inflammation repair in acute inflammation


Evidence for IL-22 Pathogenesis (Cont'd)Evidence for IL-22 Pathogenesis (Cont'd)

3.3. Chronic IBD-like disease induced in IL-22 Chronic IBD-like disease induced in IL-22 deficient mice:deficient mice:


Less epithelial hyperplasia Less epithelial hyperplasia


In chronic disease, no epithelial erosionsIn chronic disease, no epithelial erosions

Elevated IL-22 whose role is to repair leads Elevated IL-22 whose role is to repair leads to pathologic hyperplasiato pathologic hyperplasia


IL-22: Implications for RAIL-22: Implications for RA

• Cytokines may have different functions at Cytokines may have different functions at different stages of disease; in the case of IL-22different stages of disease; in the case of IL-22

Synovial damage acutely or in pre-RA?Synovial damage acutely or in pre-RA?

Synovial hyperplasia chronically?Synovial hyperplasia chronically?

• Therapeutic targets therefore may need to be Therapeutic targets therefore may need to be different depending of disease stagedifferent depending of disease stage

• Current mouse models are more consistent Current mouse models are more consistent with acute vs. chronic RAwith acute vs. chronic RA

Should we be developing chronic RA models?Should we be developing chronic RA models?


IL-33: Protective?IL-33: Protective?

• Produced by Mast cellsProduced by Mast cells

• Binds ST2 on Th2 cells (stimulatory) and soluble Binds ST2 on Th2 cells (stimulatory) and soluble ST2 (inhibitory)ST2 (inhibitory)

• Mouse model of CAD:Mouse model of CAD:

Give high levels of IL-33 Give high levels of IL-33 decreased plaque and decreased plaque and obesityobesity


IL-33: Importance in RA?IL-33: Importance in RA?

• RA patients have very high IL-33 so why do RA RA patients have very high IL-33 so why do RA patients have increased CAD???patients have increased CAD???

They also have high levels of soluble ST2 They also have high levels of soluble ST2 which inhibits IL-33 protective functionwhich inhibits IL-33 protective function

Smokers have lower levels of IL-33Smokers have lower levels of IL-33

• Take home message:Take home message:

Balance of cytokines and their receptors must Balance of cytokines and their receptors must be considered when identifying therapeutic be considered when identifying therapeutic targetstargets


BAFF and TACIBAFF and TACI

• Tolerance requires deletion of self-reactive B cellsTolerance requires deletion of self-reactive B cells

• This is an imperfect process:This is an imperfect process:

If recognizes self with high affinity, all are deletedIf recognizes self with high affinity, all are deleted

If recognizes self with low affinity, deletion occurs If recognizes self with low affinity, deletion occurs infrequentlyinfrequently

• Therefore, in all people there is a pool of low-affinity B Therefore, in all people there is a pool of low-affinity B cells that have the potential to self-reactcells that have the potential to self-react

• Most of these are marginal zone B cellsMost of these are marginal zone B cells

• These cells can be activated without T-cell help via TLR These cells can be activated without T-cell help via TLR

• Why doesn’t autoimmunity always occur after Why doesn’t autoimmunity always occur after infection??infection??


BAFF and TACI, cont'dBAFF and TACI, cont'd

• Low affinity MZ B cells upregulate TACI expression during Low affinity MZ B cells upregulate TACI expression during infectioninfection

• Findings from TACI knock-out:Findings from TACI knock-out:

MZ B cell hyperplasiaMZ B cell hyperplasia

SLE-like diseaseSLE-like disease

• Proposed mechanism during infection:Proposed mechanism during infection:

TLR4 activation leads MZ B cell to produce low-affinity Abs TLR4 activation leads MZ B cell to produce low-affinity Abs as first defense against microbesas first defense against microbes

Infection leads to macrophage and DC production of BAFFInfection leads to macrophage and DC production of BAFF

BAFF binds TACI and, in presence of TLR4 activation, leads BAFF binds TACI and, in presence of TLR4 activation, leads to upregulation of FasLto upregulation of FasL

Low-affinity MZ B cells undergo apoptosis and are deletedLow-affinity MZ B cells undergo apoptosis and are deleted


Implications of BAFF and TACI ObservationsImplications of BAFF and TACI Observations

• New mechanism of disease in SLE and/or other New mechanism of disease in SLE and/or other antibody-mediated autoimmune conditions?antibody-mediated autoimmune conditions?

• How do we identify and target the right B cells?How do we identify and target the right B cells?


29

From Bench to Bedside: New From Bench to Bedside: New Insights into Pathogenesis and Insights into Pathogenesis and Pathophysiology of Ankylosing Pathophysiology of Ankylosing

SpondylitisSpondylitis

Highlights of the EULAR Clinical Highlights of the EULAR Clinical Science Session held Wednesday, Science Session held Wednesday,

May 25May 25Summarized by Dr. Summarized by Dr. George EckerGeorge Ecker



Heiner, ANew insights into AS pathophysiology based on bone histology studies

SP0018

Rik, LMechanisms of new bone formation in animal models of AS

NA

Brown, WThe evolving role of genes and gene expression profiles in AS

SP0019

Yeremenko, NIdentification of robust and disease-specific stromal alterations in spondyloarthritis synovitis

OP0005

30Basic & Translational Science session:Cytokines with a Double Edged Sword. EULAR 2011; Wed., May 25.

Ankylosing Spondylitis from Bench to Ankylosing Spondylitis from Bench to Bedside: Key Points from the SessionBedside: Key Points from the Session

• AS is more than T-cell diseaseAS is more than T-cell disease

• There is crosstalk between inflammation and There is crosstalk between inflammation and new bone formationnew bone formation

• T- and B-cell aggregates close to cartilage in T- and B-cell aggregates close to cartilage in active AS facet jointsactive AS facet joints

• There is no major response seen with abatacept There is no major response seen with abatacept in ASin AS

Sanget, Sanget, et al: Ann Rheum Diset al: Ann Rheum Dis 2011; 70:1108. 2011; 70:1108.

• Rituximab has a positive effect in TNF-naïve AS, Rituximab has a positive effect in TNF-naïve AS, but not in TNF failuresbut not in TNF failures

Clinical Science session: From Bench to Bedside – New Insights intoPathogenesis and Pathophysiology of AS. EULAR 2011; Wed., May 25.

Ankylosing Spondylitis from Bench to Bedside: Ankylosing Spondylitis from Bench to Bedside: Key Points from the Session (Cont'd)Key Points from the Session (Cont'd)

• Active inflammation Active inflammation repair repair new bone new bone formationformation

• WNT is a pathway of new bone formationWNT is a pathway of new bone formation

• DKK1 is an inhibitor of the WNT pathwayDKK1 is an inhibitor of the WNT pathway

• Mechanisms that interfere with WNT pathway Mechanisms that interfere with WNT pathway may present potential therapeutic option to may present potential therapeutic option to prevent new bone formation in ASprevent new bone formation in AS

Clinical Science session: From Bench to Bedside – New Insights intoPathogenesis and Pathophysiology of AS. EULAR 2011; Wed., May 25.

33

Clinical Aspects of Clinical Aspects of Spondyloarthritis – What is Spondyloarthritis – What is

New?New?

Highlights of the EULAR Abstract Highlights of the EULAR Abstract Session held Thursday, May 26Session held Thursday, May 26

Summarized by Dr. Summarized by Dr. George EckerGeorge Ecker



Maksymowych, W

The Echospa MRI module for early spondyloarthritis (SpA): Which features are sufficiently reliable for evaluation of diagnosis?

OP0041

Sieper, JComparing 2 referral strategies to diagnose axial spondyloarthritis: RADAR study

OP0042

Weber, UAnterior chest wall inflammation by MRI in patients with spondyloarthritis: Frequency of involvement and association between clinical and imaging findings

OP0043

Fagerli, KThe role of CRP and peripheral disease in achieving ASDAS response to anti-TNF therapy in 308 patients with ankylosing spondylitis

OP0044

Plasencia, CInfluence of immunogenicity on the efficacy of long-term treatment with infliximab in spondyloarthrities

OP0045

Lafranchi-Debra, M –A

Comparison of axial spondylarthropathy (ASPA) and non ASPA patients rheumatologist diagnosis among an recent inflammatory back pain patients cohort? The DESIR cohort

OP0046

Weber, UErosions on MRI of the sacroiliac joints in patients with ankylosing spondylitis: Can they be reliably detected?

OP0047

Vossen, MImprovement in deployment of MR-SI in patients suspected for spondyloarthritis in a large clinical practice using a targeted intervention: A case study

OP0048

34Abstract session: Clinical Aspects of Spondyloarthritis – What is New?EULAR 2011; Thurs., May 26.

Clinical Aspects of Spondyloarthritis –Clinical Aspects of Spondyloarthritis –What is New? What is New? Highlights of the SessionHighlights of the Session

• MRI MRI (Maksymowych, Abstract #OP0041)(Maksymowych, Abstract #OP0041)

Bone edema reliable despite minimal contributionBone edema reliable despite minimal contribution

Erosions moderately reliable: capsulitis, joint Erosions moderately reliable: capsulitis, joint space narrowing can be reliably detected, lesions space narrowing can be reliably detected, lesions in ligamentus compartment NOT reliably detectedin ligamentus compartment NOT reliably detected

• Referrals Referrals (Sieper, Abstract #OP0042)(Sieper, Abstract #OP0042)

IBP, B27, sacroilitis as good as more complex IBP, B27, sacroilitis as good as more complex strategies, IBP best PPVstrategies, IBP best PPV

• Chest wall inflammation Chest wall inflammation (Weber, Abstract #OP0043)(Weber, Abstract #OP0043)

May start earlier than disease, poor agreement May start earlier than disease, poor agreement between clinical and MRI inflammationbetween clinical and MRI inflammation

Abstract session: Clinical Aspects of Spondyloarthritis – What is New?EULAR 2011; Thurs., May 26.


• Immunogenicity Immunogenicity (Plasencia, Abstract #OP0045(Plasencia, Abstract #OP0045)) Anti-infliximab-antibody-positive (anti-INF-Anti-infliximab-antibody-positive (anti-INF-

Ab+) patients have higher disease activity Ab+) patients have higher disease activity than antibody-negativethan antibody-negative

Anti-INF-Ab+ was associated with:Anti-INF-Ab+ was associated with:

– Decreased treatment survivalDecreased treatment survival

– Higher rate of infusion reactionsHigher rate of infusion reactions

– Shortened infusion intervalShortened infusion interval



• Early anti-inflammatory therapy may be key in ASEarly anti-inflammatory therapy may be key in AS

• Phase 3 study, N=76, adalimumab 40 mg eow Phase 3 study, N=76, adalimumab 40 mg eow vsvs. placebo. placebo

• ResultsResults

Ankylosis more likely to occur at sites with more advanced Ankylosis more likely to occur at sites with more advanced as compared with acute inflammatory lesionsas compared with acute inflammatory lesions

Ankylosis evident at these "sites of advanced Ankylosis evident at these "sites of advanced inflammation" despite resolution of inflammation by anti-inflammation" despite resolution of inflammation by anti-TNFTNF

In contrast, acute lesions that resolve completely with In contrast, acute lesions that resolve completely with treatment are not followed by development of ankylosistreatment are not followed by development of ankylosis

Inflammation and ankylosis become increasingly uncoupled Inflammation and ankylosis become increasingly uncoupled as inflammatory lesions matureas inflammatory lesions mature

• Conclusion: Treat earlyConclusion: Treat early


Clinical Aspects of Spondyloarthritis –Clinical Aspects of Spondyloarthritis –What is New? Highlights of the SessionWhat is New? Highlights of the Session

• MRI MRI (Weber, Abstract #OP0047)(Weber, Abstract #OP0047)

New bone formation more likely in complex New bone formation more likely in complex inflammatory lesions characterized by fat inflammatory lesions characterized by fat metaplasia where it may be uncoupled from metaplasia where it may be uncoupled from inflammationinflammation

• Prognostic significance of spinal inflammation on Prognostic significance of spinal inflammation on MRI MRI (Vossen, Abstract #OP0048)(Vossen, Abstract #OP0048)

Effective suppression of inflammation on MRI Effective suppression of inflammation on MRI important objective beyond signs and symptomsimportant objective beyond signs and symptoms

Early and effective anti-inflammatory may be Early and effective anti-inflammatory may be disease modifyingdisease modifying


Importance of Smoking in ASImportance of Smoking in AS

• DESIR cohort DESIR cohort (Lafranchi-Debra, Abstract (Lafranchi-Debra, Abstract #OP0046)#OP0046)

Smokers more likely to have:Smokers more likely to have:

– Earlier onset of inflammatory back painEarlier onset of inflammatory back pain

– Greater disease activityGreater disease activity

– Increased axial inflammationIncreased axial inflammation

– Increased axial structural damageIncreased axial structural damage

– Poorer function and worse QoLPoorer function and worse QoL


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OsteoporosisOsteoporosis

Highlights of EULAR Poster Highlights of EULAR Poster Sessions held Thursday, May 26Sessions held Thursday, May 26

Summarized by Dr. Summarized by Dr. George EckerGeorge Ecker

Efficacy and Safety of Denosumab in Efficacy and Safety of Denosumab in Osteoporosis: Lit. Review & Meta-analysisOsteoporosis: Lit. Review & Meta-analysis

• Denosumab increases BMD and reduces bone Denosumab increases BMD and reduces bone remodellingremodelling

Greater effects than alendronate, placeboGreater effects than alendronate, placebo

• Denosumab demonstrated ability to reduce Denosumab demonstrated ability to reduce vertebral, non-vertebral fracturesvertebral, non-vertebral fractures

• Tolerability concernsTolerability concerns

Increased incidence of urinary tract infection Increased incidence of urinary tract infection and rashand rash

Silva L, et al: Presented at EULAR 2011; Poster #THU0166.

Intravenous Zoledronic Acid after Subcutaneous Intravenous Zoledronic Acid after Subcutaneous Teriparatide in Postmenopausal OsteoporosisTeriparatide in Postmenopausal Osteoporosis

• Sequential s.c. teriparatide Sequential s.c. teriparatide i.v. zoledronic i.v. zoledronic acid was associated with:acid was associated with:

Stability of BMD at both lumbar spine and hipStability of BMD at both lumbar spine and hip

Increased BMD at lumbar spine: statistically Increased BMD at lumbar spine: statistically significant in comparison to oral significant in comparison to oral bisphosphonatebisphosphonate

Carlino G, et al: Presented at EULAR 2011; Poster #THU0158.

43

A Life Without BiologicsA Life Without Biologics

Highlights of a EULAR Abstract Highlights of a EULAR Abstract Session held Thursday, May 26Session held Thursday, May 26

Summarized by Dr. Summarized by Dr. Isabelle FortinIsabelle Fortin

List of Presentations in this SessionList of Presentations in this SessionSpeaker Title Abstract #

Balsa, A New drugs and new strategies for rheumatoid arthritis. A step forward NA

Weinblatt, ME

Improved health-related quality of life in patients with active rheumatoid arthritis receiving fostamatinib (R788)

OP0057

Mohamed, WDaily vs. weekly supplementation of folate in rheumatoid arthritis patients receiving weekly low-dose methotrexate (MTX)

OP0058

Fleischmann, R

The oral S1P lyase inhibitor LX3305 (aka LX2931) demonstrates favorable safety and potential clinical benefit at 12 weeks in a phase 2, proof-of-concept trial in patients with active rheumatoid arthritis on stable methotrexate therapy

OP0059

Hetland, MShort- and long-term effect of unguided, intra-articular injections with betamethasone in early rheumatoid arthritis. Impact of joint area, repeated injections, MRI findings, anti-CCP, IgM-RF and CRP

OP0060

Saleem, BPrediction of flare and long-term outcome in DMARD-treated RA patients in remission: The value of imaging and new remission criteria

OP0061

Buttgereit, FIntegrated summary of safety for modified-release prednisone compared to immediate-release prednisone: Results from the Circadian Administration of Prednisone in Rheumatoid Arthritis (CAPRA) studies

OP0062

Strand, VOral Solo (A3921045): Effects of the Oral JAK inhibitor tofacitinib (CP-690,550) monotherapy on patient-reported outcomes in a phase 3 study of active rheumatoid arthritis

OP0063

44Abstract session: A Life Without Biologics. EULAR 2011; Thurs., May 26.

A Life Without BiologicsA Life Without Biologics

• Many advances in RA treatmentMany advances in RA treatment

New drugsNew drugs

New ways of treating patientsNew ways of treating patients

• Methotrexate is the anchor drug for the Methotrexate is the anchor drug for the treatment of RAtreatment of RA

Abstract session: A Life Without Biologics. EULAR 2011; Thurs., May 26.

Combination TreatmentCombination Treatment

• EULAR does not recommend combination EULAR does not recommend combination treatmenttreatment

• The most important recommendation isThe most important recommendation isTreat to TargetTreat to Target


Yes No

SWEFOT TEAR

COBRA FIN-RACo

What About Biologics?What About Biologics?

Advantages Disadvantages

Efficacy to control symptoms Very high costs

Efficacy to control radiographic progression

Adverse events

With or without MTX

Still patients with active disease

Not available for everyone


Novel Treatments:Novel Treatments:Signal Transduction InhibitorsSignal Transduction Inhibitors

• SYK: spleen tyrosine kinaseSYK: spleen tyrosine kinase

• JAK: Janus kinaseJAK: Janus kinase

• NFkBNFkB

• MAPkMAPk

tofacitinib

fostamatinib


49

RA: Nothing is working!RA: Nothing is working!What to do?What to do?

Highlights of a EULAR Challenges Highlights of a EULAR Challenges in Clinical Practice Session held in Clinical Practice Session held

Thursday, May 26Thursday, May 26Summarized by Dr. Summarized by Dr. Isabelle FortinIsabelle Fortin

For Patients with a Disease Activity Score For Patients with a Disease Activity Score (DAS) > 5(DAS) > 5

• Are you calculating DAS?Are you calculating DAS?

Or CDAI, SDAI?Or CDAI, SDAI?

• The only association proven better than The only association proven better than monotherapy is MTX + cyclosporinemonotherapy is MTX + cyclosporine

• Prednisone is good!Prednisone is good!

Challenges in Clinical Practice Session:RA: Nothing is working! What to do?. EULAR 2011; Thurs., May 26.

Considerations for ChoosingConsiderations for Choosingan Anti-TNF Agentan Anti-TNF Agent

• Which one is the Which one is the bestbest??

• What are the patient characteristics that you What are the patient characteristics that you consider?consider?

• Why not tocilizumab or abatacept?Why not tocilizumab or abatacept?


Options for Patients Who Have Failed on Options for Patients Who Have Failed on Anti-TNF TherapyAnti-TNF Therapy

• Another anti-TNFAnother anti-TNF

• Tocilizumab Tocilizumab

• Abatacept Abatacept

• RituximabRituximab


Non-biologic Alternatives to Keep in MindNon-biologic Alternatives to Keep in Mind

• LeflunomideLeflunomide

• Cyclosporine (CIMESTRA)Cyclosporine (CIMESTRA)

• Gold saltsGold salts

• Intra-articular injectionsIntra-articular injections


54

Inflammasomes as Sentinels and Inflammasomes as Sentinels and Enemies from WithinEnemies from Within

Highlights of a EULAR Basic and Highlights of a EULAR Basic and Translational Science Session Translational Science Session

held Thursday, May 26held Thursday, May 26Summarized by Dr. Summarized by Dr. Jacob KarshJacob Karsh


Speaker TitleAbstract

#

Cawston, T Connective tissue components = immunostimulators NA

Distler, J What do animal models tell us? SP0069

Lafyatis, R Immune dysregulation in systemic sclerosis SP0070

Shiozawa, SIFN alpha as a cause of systemic lupus erythematosis and its implication to self-organized criticality theory of autoimmunity

OP0143

55Basic and Translational Science Session:Inflammasomes as Sentinels and Enemies from Within. EULAR 2011; Thurs., May 26.

The Innate Immune SystemThe Innate Immune System

• Activation of the inflammasome appears to be Activation of the inflammasome appears to be the fundamental step in the pathogenesis of the fundamental step in the pathogenesis of goutgout

It may also play a role in the development of It may also play a role in the development of atherosclerosis, type 1 diabetes, RA and other atherosclerosis, type 1 diabetes, RA and other immune diseasesimmune diseases


Immune System: PAMPs and DAMPsImmune System: PAMPs and DAMPs

• PAMPs: Pathogen-associated molecular patternsPAMPs: Pathogen-associated molecular patterns

• DAMPs: Damage-associated molecular patternsDAMPs: Damage-associated molecular patterns

• PAMPs and DAMPs intersect with cells of innate PAMPs and DAMPs intersect with cells of innate immunity via:immunity via:

a)a) Toll-like receptors (TLRs): cell surfaceToll-like receptors (TLRs): cell surface

b)b) NOD-like receptors (NLRs): cytoplasmNOD-like receptors (NLRs): cytoplasm

c)c) RIG-like receptors (RLRs): RNA from bacteria / RIG-like receptors (RLRs): RNA from bacteria / virusesviruses

d)d) Cytosolic dsDNA Sensors (CDSs): DNA from Cytosolic dsDNA Sensors (CDSs): DNA from bacteria / virusesbacteria / viruses


Four Known Inflammasome ProteinsFour Known Inflammasome Proteins

• NLRP 1NLRP 1

• NLRP 3NLRP 3

• iPAKiPAK

• AIM2AIM2


Inflammasomes in Non-myeloid CellsInflammasomes in Non-myeloid Cells

• Myeloid cells are the best studiedMyeloid cells are the best studied

• Non-myeloid cells with inflammasomesNon-myeloid cells with inflammasomes

KeratinocytesKeratinocytes

AstrocytesAstrocytes

AdiopocytesAdiopocytes

Islet cellsIslet cells


• Acne• Contact dermatitis• Psoriasis

Inflammasomes Can BeInflammasomes Can BeActivated by Non-biologic SubstancesActivated by Non-biologic Substances

• NLPR3NLPR3

Nanoparticles: sunscreen, inhaledNanoparticles: sunscreen, inhaled

Alum: vaccinesAlum: vaccines

AsbestosAsbestos

Amyloid Amyloid Alzheimer's Alzheimer's

Amylin: Islet cellsAmylin: Islet cells

Cholesterol crystalsCholesterol crystals

– Ubiquitous, and may enhance atherosclerosis via NLPR3Ubiquitous, and may enhance atherosclerosis via NLPR3

• HDL cholesterol inhibits cholesterol crystalsHDL cholesterol inhibits cholesterol crystals

• May be a more fundamental mechanism than May be a more fundamental mechanism than previously thoughtpreviously thought


Inflammasomes and Uric AcidInflammasomes and Uric Acid

• Uric acid activates inflammasomesUric acid activates inflammasomes

• Uric acid is monosodium urate (MSU) crystalsUric acid is monosodium urate (MSU) crystals

Most of crystal is sodiumMost of crystal is sodium

When MSU is phagocytosed, high amounts of sodium are When MSU is phagocytosed, high amounts of sodium are introduced into the cellintroduced into the cell

The phagocytic vesicle (lysoome) needs to acidify to The phagocytic vesicle (lysoome) needs to acidify to release MSU into the cytoplasm; this in turn leads to high release MSU into the cytoplasm; this in turn leads to high intracellular Na+intracellular Na+

– To deal with this, the cell ingests HTo deal with this, the cell ingests H220, which leads to 0, which leads to dilution of K+, which is required to activate NLPR3dilution of K+, which is required to activate NLPR3

HCQ / chloroquine prevents lysosomal acidificationHCQ / chloroquine prevents lysosomal acidification


62

Bone and Crystal DiseasesBone and Crystal Diseases


Summarized by Dr. Summarized by Dr. Jacob KarshJacob Karsh

List of Presentations in this SessionList of Presentations in this SessionSpeaker Title Abstract #

Schlesinger, NEfficacy of canankinumab vs. triamcinolone acetonide in preventing recurrent flares in acute gouty arthritis patients contraindicated, intolerant or unresponsive to NSAIDs and/or colchicine: Results from two pivotal studies.

OP0107

So, AA controlled trial of canakinumab vs. triamcinolone acetonide in acute gouty arthritis patients: Results of the ?-RELIEVED study (response in acute flare and in prevention of episodes of re-flare in gout).

OP0108

Ottaviani, S Ultrasonography findings in gouty patients: A case-control study. OP0109

Richette, P Effect of massive weight loss on serum uric acid levels OP0110

Perez-Ruiz, FEfficacy and safety of lesinurad (RDEA594), a novel uricosuric agent, given in combination with allopurinol in allopurinol-refractory gout patients: Randomized, double-blind, placebo-controlled, phase 2B study

OP0111

Nuki, GChronic gout in Europe in 2010: Clinical profile of 1,380 patients in the UK, Germany, France, Italy and Spain

OP0112

Lipsky, PSafety and efficacy of long-term pegloticase (Krystexya?) treatment in adult patients with chronic gout refractory to conventional therapy

OP0113

Lee, Y-A Tight serum urate control may improve renal dysfunction in patients with gout OP0114

63Abstract Session: Bone and crystal diseases. EULAR 2011; Thurs., May 26.

Common Themes in the Abstract SessionCommon Themes in the Abstract Session

• Hyperuricemia / gout is poorly treatedHyperuricemia / gout is poorly treated

Goal should be to bring uric acid below level Goal should be to bring uric acid below level where urate is soluble – 6 mg/dL or 360 where urate is soluble – 6 mg/dL or 360 μμM/LM/L

• Global increase in goutGlobal increase in gout

Prevalence of gout is 1.4% in UKPrevalence of gout is 1.4% in UK

Treatment is 7% of men and 3% of women > Treatment is 7% of men and 3% of women > 75 years75 years


Common Themes in the Abstract Session: Common Themes in the Abstract Session: UndertreatmentUndertreatment

• Few patients on allopurinol have dose > 300 Few patients on allopurinol have dose > 300 mg/dmg/d

Best was UK, where 19% had > 300 mg, Best was UK, where 19% had > 300 mg, ascribed to NICE recommendationsascribed to NICE recommendations

• <2% used uricosurics<2% used uricosurics

• Only 1/3 of patients had serum uric acid < 360 Only 1/3 of patients had serum uric acid < 360 μμM/LM/L

• Overall, 18% received > 300 mg/d allopurinol or Overall, 18% received > 300 mg/d allopurinol or > 80 mg febuxostat and still had uncontrolled > 80 mg febuxostat and still had uncontrolled goutgout

• A treat-to-target approach is neededA treat-to-target approach is needed


Common Themes in the Abstract Session: Common Themes in the Abstract Session: UndertreatmentUndertreatment

• Reasons for reticence in higher doses of allopurinolReasons for reticence in higher doses of allopurinol

Renal insufficiencyRenal insufficiency

Fear of AEs, especially hypersensitivityFear of AEs, especially hypersensitivity

– Hypersensitivity reactions found to be related Hypersensitivity reactions found to be related to baseline renal function and allopurinol to baseline renal function and allopurinol starting dose starting dose

• Nephros / rheums were no better than family Nephros / rheums were no better than family doctors: urged to be more aggressivedoctors: urged to be more aggressive

In patients with normal renal function, increasing In patients with normal renal function, increasing allopurinol dose to as high as 600 mg/d led to allopurinol dose to as high as 600 mg/d led to 95% success in reducing SUA to < 360 95% success in reducing SUA to < 360 μμM/LM/L


Effect of Massive Weight Loss on Serum Uric AcidEffect of Massive Weight Loss on Serum Uric Acid

• EULAR recommends weight loss as part of EULAR recommends weight loss as part of treatmenttreatment

However, weight loss of 10 kg results in only a However, weight loss of 10 kg results in only a very small reduction in UAvery small reduction in UA

• In an investigation of the effects of bariatric surgery In an investigation of the effects of bariatric surgery (n=152 patients, mostly women, without gout):(n=152 patients, mostly women, without gout):

Patients lost 20-30 kgPatients lost 20-30 kg

Change in serum uric acid: from mean of 331 Change in serum uric acid: from mean of 331 μμM/L to 299 M/L to 299 μμM/LM/L

Best correlate of reduced UA was reduced TGBest correlate of reduced UA was reduced TG

67Richette P, et al: Presented at EULAR 2011; Presentation #OP0110.

Effect of Lesinurad in Allopurinol-refractory GoutEffect of Lesinurad in Allopurinol-refractory Gout

• Lesinurad inhibits URAT1 in the proximal tubule, OAT4 Lesinurad inhibits URAT1 in the proximal tubule, OAT4 transportertransporter

• In two separate studies, investigated in combination with In two separate studies, investigated in combination with allopurinol or with febuxostat versus either agent in allopurinol or with febuxostat versus either agent in monotherapymonotherapy

Doses studied: 400 & 600 mg: in combination with stable Doses studied: 400 & 600 mg: in combination with stable allopurinol 200 – 600 and febuxostat 40 and 80allopurinol 200 – 600 and febuxostat 40 and 80

Lesinurad was found to be:Lesinurad was found to be:

– Very effective at achieving normal SUA levels in Very effective at achieving normal SUA levels in combination with allopurinol or febuxostatcombination with allopurinol or febuxostat

• Febuxostat combination better than the allopurinol Febuxostat combination better than the allopurinol combinationcombination

• Patients receiving concomitant HCTZ fared better Patients receiving concomitant HCTZ fared better than those not receiving HCTZthan those not receiving HCTZ

68Perez-Ruiz F, et al: Presented at EULAR 2011; Presentation #OP0111.

Novel Agents: BCX4208Novel Agents: BCX4208

• BCX 4208 is a novel enzyme inhibitor of Purine BCX 4208 is a novel enzyme inhibitor of Purine Nucleoside Phosphorylase (PNP)Nucleoside Phosphorylase (PNP)

Blocks the generation of precursors of uric Blocks the generation of precursors of uric acid at a higher level in the metabolic pathway acid at a higher level in the metabolic pathway than xanthine oxidase inhibitorsthan xanthine oxidase inhibitors

• When added to allopurinol, synergistic When added to allopurinol, synergistic reduction in serum UA, with 100% of patients reduction in serum UA, with 100% of patients achieving SUA < 6 mg/dLachieving SUA < 6 mg/dL


Novel Agents: PegloticaseNovel Agents: Pegloticase

• Placebo-controlled study, followed by open-label Placebo-controlled study, followed by open-label extensionextension

85 patients treated with 8 mg i.v. q 2 weeks in 6-85 patients treated with 8 mg i.v. q 2 weeks in 6-month placebo-controlled phasemonth placebo-controlled phase

– 36 entered the open-label extension36 entered the open-label extension

• For those capable of continuing, SUA For those capable of continuing, SUA was reduced < 2 mg/dL with significant was reduced < 2 mg/dL with significant reduction in flares, tophi, tender & reduction in flares, tophi, tender & swollen jointsswollen joints

• Infusion reactions 0.4% in persistent Infusion reactions 0.4% in persistent responders, 4.2% in those with responders, 4.2% in those with antibodiesantibodies

70Lipsky P, et al: Presented at EULAR 2011; Presentation #OP0113.

Uric Acid and Kidney DiseaseUric Acid and Kidney Disease

• High uric acid is an independent risk factor for High uric acid is an independent risk factor for kidney diseasekidney disease

There is too much worry regarding the use of There is too much worry regarding the use of allopruinol in patients with renal insufficiencyallopruinol in patients with renal insufficiency

• Study of 370 patients with gout investigated the Study of 370 patients with gout investigated the prevalence of renal insufficienceprevalence of renal insufficience

92 had GFR 30-59 (moderate)92 had GFR 30-59 (moderate)

29 had GFR 15-29 (severe)29 had GFR 15-29 (severe)

Tight control of serum UA (≤ 6 mg/dL) was Tight control of serum UA (≤ 6 mg/dL) was associated with improvement in renal associated with improvement in renal function function

71Lee Y-A, et al: Presented at EULAR 2011; Presentation #OP0114.

Canakinumab for Treatment of Acute GoutCanakinumab for Treatment of Acute Gout

• B-RELIEVED and B-RELIEVED 2B-RELIEVED and B-RELIEVED 2

Parallel, 12-week studies in patients with Parallel, 12-week studies in patients with gout, intolerant of, unresponsive to or with gout, intolerant of, unresponsive to or with contraindication for NSAIDs and/or colchicinecontraindication for NSAIDs and/or colchicine

Subjects treated with single injection of Subjects treated with single injection of canakinumab 50 mg s.c. or triamcinolone 40 canakinumab 50 mg s.c. or triamcinolone 40 mg i.m.mg i.m.

72Schlesinger N, et al: Presented at EULAR 2011; Presentation #OP0107.So S, et al: Presented at EULAR 2011; Presentation #OP0108.

Canakinumab for Treatment of Acute GoutCanakinumab for Treatment of Acute Gout

• Results of BELIEVE & BELIEVE 2:Results of BELIEVE & BELIEVE 2:

High completion rate (>90%)High completion rate (>90%)

Flares reduced 55-68% at 12 weeksFlares reduced 55-68% at 12 weeks

Pain significantly reduced at 72 hoursPain significantly reduced at 72 hours

– Reduction of 40 mm on a 100 mm VAS with Reduction of 40 mm on a 100 mm VAS with canakinumab vs. 28 mm with triamcinolonecanakinumab vs. 28 mm with triamcinolone

– Decrease in joint tendernessDecrease in joint tenderness

– No major side effectsNo major side effects

– Higher number of infections with canakinumab Higher number of infections with canakinumab

73Schlesinger N, et al: Presented at EULAR 2011; Presentation #OP0107.So S, et al: Presented at EULAR 2011; Presentation #OP0108.

74

VasculitisVasculitis


Summarized by Dr. Summarized by Dr. Nader KhalidiNader Khalidi

Long-term Efficacy of Rituximab in ANCA-Long-term Efficacy of Rituximab in ANCA-associated Vasculitis (RAVE trial)associated Vasculitis (RAVE trial)

• Objectives: To evaluate efficacy and safety of one course of RTX in Objectives: To evaluate efficacy and safety of one course of RTX in comparison to CYC followed by AZA over the course of 18 monthscomparison to CYC followed by AZA over the course of 18 months

• Methods: Methods:

Multicenter, randomized, double-blind, placebo-controlled trial Multicenter, randomized, double-blind, placebo-controlled trial

RTX (375 mg/mRTX (375 mg/m22 iv weekly x 4) versus CYC (2 mg/kg/d po) iv weekly x 4) versus CYC (2 mg/kg/d po)

Followed for a minimum of 18 months Followed for a minimum of 18 months

Patients received 1-3 g iv methylprednisolone followed by Patients received 1-3 g iv methylprednisolone followed by prednisone 1 mg/kg/d, tapered over 5.5 monthsprednisone 1 mg/kg/d, tapered over 5.5 months

CYC was replaced by AZA between months 3-6 if remission was CYC was replaced by AZA between months 3-6 if remission was achieved, and AZA was continued through 18 monthsachieved, and AZA was continued through 18 months

The RTX group received placebo after 3-6 months if remission had The RTX group received placebo after 3-6 months if remission had been achievedbeen achieved

All data shown were based on intention-to-treat analyses with All data shown were based on intention-to-treat analyses with worst case imputationworst case imputation

Stone J, et al: Presented at EULAR 2011; Oral Presentation #OP0054.


• Results: Results:

197 ANCA-positive patients were enrolled197 ANCA-positive patients were enrolled

Mean follow-up: 35 months (SD, 14.6). Mean follow-up: 35 months (SD, 14.6).

The primary outcome at 6 months (BVAS/WG and The primary outcome at 6 months (BVAS/WG and prednisone=0) was achieved by prednisone=0) was achieved by

• 64% of the patients assigned to RTX64% of the patients assigned to RTX

• 53% in the CYC arm (53% in the CYC arm (p p = 0.13)= 0.13)

At 12 and 18 months, At 12 and 18 months,

• 42% and 36% in the RTX arm versus 38% and 31% in the 42% and 36% in the RTX arm versus 38% and 31% in the CYC arm remained in remission off glucocorticoids (CYC arm remained in remission off glucocorticoids (p p = = NS)NS)

The number flares, the number of patients suffering at least The number flares, the number of patients suffering at least one flare, and the flare rates did not differ between treatment one flare, and the flare rates did not differ between treatment arms over 18 months (arms over 18 months (p p = NS)= NS)



• Results (cont'd): Results (cont'd):

Relapses were more common among PR3-ANCA positive Relapses were more common among PR3-ANCA positive patients than MPO-ANCA positive patientspatients than MPO-ANCA positive patients

Average cumulative glucocorticoid dose was significantly Average cumulative glucocorticoid dose was significantly lower in the RTX arm by 12 months (RTX 3270 mg versus lower in the RTX arm by 12 months (RTX 3270 mg versus control 3678 mg, control 3678 mg, p p = 0.031), but no longer by 18 months = 0.031), but no longer by 18 months (RTX 3541 versus control 3956, (RTX 3541 versus control 3956, p p = 0.088)= 0.088)

There was no difference in overall, serious or selected There was no difference in overall, serious or selected adverse events rates between the treatment arms at 18 adverse events rates between the treatment arms at 18 months or through common close-outmonths or through common close-out


In patients with severe AAV, a single course of RTX is as In patients with severe AAV, a single course of RTX is as effective as 18 months of standard therapy for remission effective as 18 months of standard therapy for remission induction and maintenanceinduction and maintenance


Two-year Follow-up Results From a Randomized Trial of RTX Two-year Follow-up Results From a Randomized Trial of RTX Vs. CYC for ANCA-associated Renal Vasculitis: RITUXVASVs. CYC for ANCA-associated Renal Vasculitis: RITUXVAS

• Background:Background:

CYC-based induction regimens are standard therapy for ANCA-CYC-based induction regimens are standard therapy for ANCA-AAVr; however, associated mortality and adverse event rates are AAVr; however, associated mortality and adverse event rates are high and safer regimens are requiredhigh and safer regimens are required

RTX-based regimens are a potential alternative to CYC inductionRTX-based regimens are a potential alternative to CYC induction

• Methods:Methods:

2-year results of a randomized trial comparing a RTX-based 2-year results of a randomized trial comparing a RTX-based induction regimen with a standard intravenous CYC regimen for induction regimen with a standard intravenous CYC regimen for new AAVrnew AAVr

All patients had newly diagnosed AAVr and ANCA positivity. All patients had newly diagnosed AAVr and ANCA positivity.

44 patients were randomized:44 patients were randomized:

• 33 to RTX 4 × 375 mg/m2 and 2 × 15 mg/kg i.v. CYC; and 33 to RTX 4 × 375 mg/m2 and 2 × 15 mg/kg i.v. CYC; and

• 11 to i.v. CYC 6–10 × 15 mg/kg.11 to i.v. CYC 6–10 × 15 mg/kg.

Both groups received the same i.v. and oral prednisolone regimenBoth groups received the same i.v. and oral prednisolone regimen

Jones RB, et al: Clin Exp Immunol 2011; (suppl.1):57.



At entry, median age was 68 years; GPA 50%, MPA At entry, median age was 68 years; GPA 50%, MPA 50%; CRP 28; 50%; CRP 28; BVAS 18; PR3-ANCA 57%, MPO-ANCA 43%, BVAS 18; PR3-ANCA 57%, MPO-ANCA 43%, GFR 18 ml/min; 20% GFR 18 ml/min; 20% required dialysis. required dialysis.

At 2 years:At 2 years:

– The primary composite outcome of relapse, death or ESRF The primary composite outcome of relapse, death or ESRF occurred in 14 of 33 (42%) RTX occurred in 14 of 33 (42%) RTX vsvs. 4 of 11 (36%) CYC (. 4 of 11 (36%) CYC (pp = 1.00) = 1.00)

– Relapse occurred in 7 of 33 (21%) RTX Relapse occurred in 7 of 33 (21%) RTX vsvs. 2 of 11 (18%) CYC (. 2 of 11 (18%) CYC (pp = = 1.00)1.00)

– Death occurred in 6 of 33 (18%) RTX Death occurred in 6 of 33 (18%) RTX vs.vs. 3 of 11 (27%) CYC ( 3 of 11 (27%) CYC (pp = = 0.67) 0.67)

– ESRF occurred in 2 of 33 (6%) RTX ESRF occurred in 2 of 33 (6%) RTX vs.vs. 0 of 11 (0%) CYC ( 0 of 11 (0%) CYC (pp = 0.57) = 0.57)

Median estimated GFR was 20 and 44 mL/min/mMedian estimated GFR was 20 and 44 mL/min/m22 in RTX patients at in RTX patients at 0 and 24 months, respectively, 0 and 24 months, respectively, vs.vs. 12 and 31 mL/min/m 12 and 31 mL/min/m22 in CYC in CYC patientspatients



• Results (Cont'd): Results (Cont'd):

Serious adverse events (SAEs) occurred in Serious adverse events (SAEs) occurred in

– 61% RTX (50 events, 20 of 33 patients) 61% RTX (50 events, 20 of 33 patients)

– 36% CYC (15 events, 4 of 11 patients) 36% CYC (15 events, 4 of 11 patients)

• Incidence rate ratio 1.16; 95% CI 0.64–Incidence rate ratio 1.16; 95% CI 0.64–2.22) (2.22) (pp = 0.64) = 0.64)



• Conclusions: Conclusions:

RTX-based induction therapy is efficacious, RTX-based induction therapy is efficacious, but is not superior to i.v. CYC at 2 years in but is not superior to i.v. CYC at 2 years in terms of combined relapse, mortality and terms of combined relapse, mortality and ESRF outcomeESRF outcome

Further strategies to reduce mortality and Further strategies to reduce mortality and SAEs and prevent relapse should be SAEs and prevent relapse should be consideredconsidered


Long-term Renal Outcome of Patients Enrolled in theLong-term Renal Outcome of Patients Enrolled in theCYCAZAREM TrialCYCAZAREM Trial

• Objective:Objective:

Long-term renal outcome of patients enrolled Long-term renal outcome of patients enrolled in the CYCAZAREM trialin the CYCAZAREM trial


Long term follow-up data of CYCAZAREM Long term follow-up data of CYCAZAREM patients were acquired from a questionnaire patients were acquired from a questionnaire completed by all participating physicianscompleted by all participating physicians

Berden A, et al: Clin Exp Immunol 2011; (suppl.1):51.

Long-term Renal Outcome of Patients Enrolled in theLong-term Renal Outcome of Patients Enrolled in theCYCAZAREM TrialCYCAZAREM Trial

• Results: Data on ESRD were available for 130 of 155 Results: Data on ESRD were available for 130 of 155 patients enrolled originally in the trial.patients enrolled originally in the trial.

Mean ± s.d. follow-up was 7.09 ± 3.14 yearsMean ± s.d. follow-up was 7.09 ± 3.14 years

In the oral CYC treatment arm, 6 of 65 (9%) In the oral CYC treatment arm, 6 of 65 (9%) developed ESRD during follow-up, compared to 8 developed ESRD during follow-up, compared to 8 of 65 (12%) in the AZA arm (n.s.)of 65 (12%) in the AZA arm (n.s.)

Mean ± s.d. eGFR at 5 years was 49.0 ± 29.9 Mean ± s.d. eGFR at 5 years was 49.0 ± 29.9 mL/min in the AZA arm compared to 50.9 ± 25.1 mL/min in the AZA arm compared to 50.9 ± 25.1 mL/min in the oral CYC arm (n.s.)mL/min in the oral CYC arm (n.s.)

• Conclusion: Azathioprine is as effective as oral CYC Conclusion: Azathioprine is as effective as oral CYC maintenance therapy in ANCA-associated vasculitis maintenance therapy in ANCA-associated vasculitis when regarding long-term renal outcome, when regarding long-term renal outcome, supporting its usesupporting its use

Berden A, et al: Clin Exp Immunol 2011; (suppl.1):51.

Pulse Versus Daily Oral CYC for Induction of Remission in ANCA-Pulse Versus Daily Oral CYC for Induction of Remission in ANCA-associated Vasculitis. associated Vasculitis. A European, Multi-centre Randomized Controlled A European, Multi-centre Randomized Controlled TTrial: Long-term Follow-up (CYCLOPS)rial: Long-term Follow-up (CYCLOPS)


Describe the long-term patient survival and relapse rates of Describe the long-term patient survival and relapse rates of patients recruited to the CYCLOPS studypatients recruited to the CYCLOPS study


Questionnaire was sent to the CYCLOPS participating Questionnaire was sent to the CYCLOPS participating physiciansphysicians

Data on survival, renal survival, relapse rate, Data on survival, renal survival, relapse rate, immunosuppressive therapy, cancer rate, bone fractures, immunosuppressive therapy, cancer rate, bone fractures, thromboembolic disease and cardiovascular morbidity were thromboembolic disease and cardiovascular morbidity were recordedrecorded

Returns were received on 134 of 149 patients recruited to Returns were received on 134 of 149 patients recruited to the original studythe original study

Analyses were performed by intention-to treatAnalyses were performed by intention-to treat

Harper L, et al: Clin Exp Immunol 2011; (suppl.1):56.



Median duration of follow-up was 4.3 years (IQR Median duration of follow-up was 4.3 years (IQR 2.95–5.44 years), with no difference between the 2.95–5.44 years), with no difference between the two arms (two arms (pp = 0.5) = 0.5)

12 patients in the daily oral and 13 in the pulse 12 patients in the daily oral and 13 in the pulse arm died during follow-up; median time to death arm died during follow-up; median time to death was 813 days (IQR 117–1143), with no difference was 813 days (IQR 117–1143), with no difference between the two arms (between the two arms (pp = 0.94) = 0.94)

44 patients (29 pulse and 15 daily oral) had 67 44 patients (29 pulse and 15 daily oral) had 67 relapses, 28 of which were renalrelapses, 28 of which were renal

The time to relapse was significantly longer in the The time to relapse was significantly longer in the daily oral arm (HR = 0.51, 95% CI: 0.27–0.95; daily oral arm (HR = 0.51, 95% CI: 0.27–0.95; pp = = 0.033)0.033)



• Results (cont'd):Results (cont'd):

Patients who were PR3-anti-ANCA positive at Patients who were PR3-anti-ANCA positive at diagnosis were more likely to relapse than those diagnosis were more likely to relapse than those who were not PR3-ANCA-positive (HR = 0.49, 95% who were not PR3-ANCA-positive (HR = 0.49, 95% CI: 0.27–0.91)CI: 0.27–0.91)

Despite a reduced time to relapse there was no Despite a reduced time to relapse there was no difference in renal function (pulse median 116, IQR difference in renal function (pulse median 116, IQR 89–185, DO median 119, IQR 102–143; P = 0.84), 89–185, DO median 119, IQR 102–143; P = 0.84), adverse events, total dose of immunosuppression adverse events, total dose of immunosuppression or VDI between the two armsor VDI between the two arms

• Conclusion: Pulse cyclophosphamide is associated Conclusion: Pulse cyclophosphamide is associated with a higher relapse rate than daily oral with a higher relapse rate than daily oral cyclophosphamide; however, this is not associated cyclophosphamide; however, this is not associated with increased death or worse renal functionwith increased death or worse renal function


Protocolized Versus Non-protocolized RTX TreatmentProtocolized Versus Non-protocolized RTX Treatmentfor Refractory ANCA-AAVfor Refractory ANCA-AAV


Single-centre study comparing 6-monthly, Single-centre study comparing 6-monthly, protocolized RTX retreatment and non-protocolized RTX retreatment and non-protocolized RTX retreatment according to protocolized RTX retreatment according to clinical need for refractory AAVclinical need for refractory AAV


49 patients received a protocolized RTX regimen:49 patients received a protocolized RTX regimen:

– 1 g × 2 followed by 1 g × 1 q 6 months for 2 1 g × 2 followed by 1 g × 1 q 6 months for 2 years (5 g total) with early immunosuppression years (5 g total) with early immunosuppression and corticosteroid withdrawaland corticosteroid withdrawal

34 received non-protocolized RTX; either 1 g × 2 34 received non-protocolized RTX; either 1 g × 2 or 375 mg/mor 375 mg/m22 × 4 only repeated at relapse × 4 only repeated at relapse




At first RTX, median disease duration was 55 months: previous At first RTX, median disease duration was 55 months: previous cyclophosphamide exposure was 14 gcyclophosphamide exposure was 14 g

RTX indication was relapsing disease in 90% of protocol and 82% RTX indication was relapsing disease in 90% of protocol and 82% of non-protocol patients; the remainder had grumbling disease of non-protocol patients; the remainder had grumbling disease while receiving continuous high-dose corticosteroids or while receiving continuous high-dose corticosteroids or immunosuppressionimmunosuppression

Median follow-up was 25 (4–46) months for protocol patients, Median follow-up was 25 (4–46) months for protocol patients, versus 22 (6–84) months for non-protocol patientsversus 22 (6–84) months for non-protocol patients

Response to RTX occurred in 47 of 49 (96%) protocol patients Response to RTX occurred in 47 of 49 (96%) protocol patients (90% full remission, 6% partial) and 32 of 34 (94%) non-protocol (90% full remission, 6% partial) and 32 of 34 (94%) non-protocol patients (82% full remission, 12% partial)patients (82% full remission, 12% partial)

In protocol patients only 3 of 48 (6%) were still receiving In protocol patients only 3 of 48 (6%) were still receiving immunosuppression at 6 months, and by 24 months 22% had immunosuppression at 6 months, and by 24 months 22% had withdrawn from prednisolone (4.25 mg/ day median)withdrawn from prednisolone (4.25 mg/ day median)



• Results (cont'd): Results (cont'd):

At 2 years, relapse had occurred in:At 2 years, relapse had occurred in:

– 11 of 49 (22%) protocol patients 11 of 49 (22%) protocol patients

– 24 of 34 (71%) non-protocol patients24 of 34 (71%) non-protocol patients

At end of follow-up, relapse had occurred in:At end of follow-up, relapse had occurred in:

– 3 of 49 (27%) protocol patients3 of 49 (27%) protocol patients

– 26 of 34 (76%) non-protocol patients (26 of 34 (76%) non-protocol patients (pp < 0.01) < 0.01)

Serious infections occurred in:Serious infections occurred in:

– 14% of protocol patients 14% of protocol patients

– 18% of non-protocol patients18% of non-protocol patients



• Conclusion: Conclusion:

Six-monthly protocolized RTX retreatment is Six-monthly protocolized RTX retreatment is effective for relapse prevention, allows effective for relapse prevention, allows immunosuppression withdrawal and appears safe immunosuppression withdrawal and appears safe in refractory AAVin refractory AAV


Rituximab Provides Stable Long-term Rituximab Provides Stable Long-term Responses in ANCA-associated VasculitisResponses in ANCA-associated Vasculitis

• Background: Background:

Randomized clinical trials have demonstrated that rituximab (RTX) Randomized clinical trials have demonstrated that rituximab (RTX) is an effective treatment for ANCA Associated Systemic Vasculitis is an effective treatment for ANCA Associated Systemic Vasculitis (AASV), with primary clinical outcome at 6 months(AASV), with primary clinical outcome at 6 months

Some protocols have specified fixed repeat treatment at 6 monthsSome protocols have specified fixed repeat treatment at 6 months

However, there are fewer data regarding longer term outcomes However, there are fewer data regarding longer term outcomes after RTX, including duration of response, patterns of relapse and after RTX, including duration of response, patterns of relapse and the basis for the timing of repeat treatmentthe basis for the timing of repeat treatment

• Objectives:Objectives:

To identify patterns of response and relapse after RTX for AASV To identify patterns of response and relapse after RTX for AASV

To identify potential biomarkers of response to guide decisions To identify potential biomarkers of response to guide decisions regarding timing of repeat cycles of RTXregarding timing of repeat cycles of RTX

Dass S, et al: Presented at EULAR 2011; Oral Presentation #OP0049.



Prospective study of patients with active AASV treated with Prospective study of patients with active AASV treated with RTX 1g and methylprednisolone 100mg x 2 infusions on RTX 1g and methylprednisolone 100mg x 2 infusions on Days 1 and 15Days 1 and 15

• Also received oral prednisolone 60mg daily (1 week) and Also received oral prednisolone 60mg daily (1 week) and 30mg (1 week) between infusions to minimise infusion 30mg (1 week) between infusions to minimise infusion reactions and incidence of serum sicknessreactions and incidence of serum sickness

Disease activity was assessed by BVAS 3.0 at baseline and Disease activity was assessed by BVAS 3.0 at baseline and every 3 months post therapyevery 3 months post therapy

Responders were maintained on stable or reducing levels of Responders were maintained on stable or reducing levels of immunosuppression (including oral steroid)immunosuppression (including oral steroid)

Repeat treatment was given on clinical diagnosis of relapseRepeat treatment was given on clinical diagnosis of relapse

Follow up after the 2nd cycle of RTX was as for the 1st Follow up after the 2nd cycle of RTX was as for the 1st cyclecycle




22 patients were treated (18 GPA, 3 pANCA vasculitis, 1 22 patients were treated (18 GPA, 3 pANCA vasculitis, 1 Churg Strauss): all were ANCA positive before RTXChurg Strauss): all were ANCA positive before RTX

Most common organ systems: ENT (77%), renal (55%) and Most common organ systems: ENT (77%), renal (55%) and arthritis and pulmonary (45% each)arthritis and pulmonary (45% each)

18 patients had received cyclophosphamide previously 18 patients had received cyclophosphamide previously (withdrawn in 16 due to lack of efficacy); baseline mean (withdrawn in 16 due to lack of efficacy); baseline mean BVAS score was 9.9 (SD 5.1)BVAS score was 9.9 (SD 5.1)

13 patients were maintained on concomitant 13 patients were maintained on concomitant immunosuppression with DMARDsimmunosuppression with DMARDs

Total patient follow-up was 3288 weeks; median follow up Total patient follow-up was 3288 weeks; median follow up was 137 weeks (range 35-263 weeks)was 137 weeks (range 35-263 weeks)




Mean BVAS at week 26 was 1.2 (SD 0.5, Mean BVAS at week 26 was 1.2 (SD 0.5, pp = 0.003) = 0.003)

At week 26, 11 patients had complete response, 9 patients had partial At week 26, 11 patients had complete response, 9 patients had partial responseresponse

Relapse:Relapse:

– Median time to relapse was 89 weeksMedian time to relapse was 89 weeks

– Patients with partial response relapsed earlier than those with Patients with partial response relapsed earlier than those with complete response (81 vs 120 weeks, partial vs complete complete response (81 vs 120 weeks, partial vs complete response, response, pp = 0.03) = 0.03)

The duration of response for cycles 1 and 2 of RTX showed The duration of response for cycles 1 and 2 of RTX showed significant correlation (significant correlation (rr = 0.709, = 0.709, p =p = 0.022) 0.022)

Median dose of daily oral prednisone was reduced from 15mg Median dose of daily oral prednisone was reduced from 15mg (baseline) to 6.3 mg (week 26) and 4.3 mg (relapse)(baseline) to 6.3 mg (week 26) and 4.3 mg (relapse)

No patient relapsed in the absence of peripheral blood B cellsNo patient relapsed in the absence of peripheral blood B cells

– However, levels of B cell depletion or repopulation did not predict However, levels of B cell depletion or repopulation did not predict response or subsequent relapseresponse or subsequent relapse




1.1. RTX is an effective therapy for severe, active AASVRTX is an effective therapy for severe, active AASV

2.2. Responses are long, often considerably greater than 24 Responses are long, often considerably greater than 24 weeks and are longer in those with complete clinical weeks and are longer in those with complete clinical responseresponse

3.3. Disease activity at relapse is often less than at baselineDisease activity at relapse is often less than at baseline

4.4. This suggests that retreatment with RTX on relapse may be This suggests that retreatment with RTX on relapse may be more appropriate than a fixed retreatment regime eg given more appropriate than a fixed retreatment regime eg given at 6 months. Decisions regarding the timing of retreatment at 6 months. Decisions regarding the timing of retreatment may be guided more accurately by the duration of response may be guided more accurately by the duration of response to the 1st cycle of RTXto the 1st cycle of RTX

5.5. A biomarker that predicts response and relapse is still to be A biomarker that predicts response and relapse is still to be identifiedidentified


Retrospective Study of Rituximab in Refractory Granulomatosis with Retrospective Study of Rituximab in Refractory Granulomatosis with Polyangiitis (Wegener's): Comparison of Treatment Response in Polyangiitis (Wegener's): Comparison of Treatment Response in Vasculitic Versus Granulomatous ManifestationsVasculitic Versus Granulomatous Manifestations


To determine the overall efficacy of RTX in To determine the overall efficacy of RTX in refractory WG in a monocentric retrospective study refractory WG in a monocentric retrospective study of 75 casesof 75 cases

To compare the efficacy of RTX in granulomatous To compare the efficacy of RTX in granulomatous versus vasculitic manifestationsversus vasculitic manifestations


All patients received RTX with or without additional All patients received RTX with or without additional conventional immunosuppressants for refractory conventional immunosuppressants for refractory GPA from 2002 to 2010 (4x 375 mg/mGPA from 2002 to 2010 (4x 375 mg/m22 four times in four times in weekly intervals)weekly intervals)

Side effects, duration of remission and relapses Side effects, duration of remission and relapses were also documentedwere also documented

Holle J, et al: Presented at EULAR 2011; Oral Presentation #OP0055.



59 GPA patients received 75 cycles of RTX for 59 GPA patients received 75 cycles of RTX for refractory manifestations, 66% due to granulomatous refractory manifestations, 66% due to granulomatous and/or 39% due to vasculitic manifestationsand/or 39% due to vasculitic manifestations

Follow-up of at least 4 months, 9.33% had a complete Follow-up of at least 4 months, 9.33% had a complete remission, 52% a response, 9.33% an unchanged remission, 52% a response, 9.33% an unchanged activity and 26.66% a disease progressionactivity and 26.66% a disease progression

Prednisolone dose, BVAS and B-cell counts Prednisolone dose, BVAS and B-cell counts decreased significantly (decreased significantly (pp < 0.05) after RTX treatment < 0.05) after RTX treatment

Response rates (complete remission plus response) of Response rates (complete remission plus response) of vasculitic manifestations were excellent and vasculitic manifestations were excellent and significantly higher compared to granulomatous significantly higher compared to granulomatous manifestation such as orbital granuloma and manifestation such as orbital granuloma and pachymeningitis (pachymeningitis (pp < 0.05) < 0.05)



• Results (Cont’d): Results (Cont’d):

In patients with alveolar hemorrhage (n=12) or In patients with alveolar hemorrhage (n=12) or refractory active renal disease (n=26), there were refractory active renal disease (n=26), there were 83.3% and 80.1% complete remissions/responses83.3% and 80.1% complete remissions/responses

In 27 patients with orbital granuloma, there were In 27 patients with orbital granuloma, there were no complete remissions, 44.4% responses, 22.2% no complete remissions, 44.4% responses, 22.2% with unchanged activity and 33.3% with with unchanged activity and 33.3% with progressionprogression

2 patients died, the infection rate was 21% and 2 patients died, the infection rate was 21% and relapse was frequent (40% after a median follow-relapse was frequent (40% after a median follow-up of 13.5 months, range 3-54 months)up of 13.5 months, range 3-54 months)

Re-treatment after relapse was effectiveRe-treatment after relapse was effective




1.1. Overall efficacy of RTX in refractory GPA was Overall efficacy of RTX in refractory GPA was good (around 61.3% complete remissions or good (around 61.3% complete remissions or improvement)improvement)

2.2. Response rates of vasculitic manifestations were Response rates of vasculitic manifestations were excellent; treatment failure or progress occurred excellent; treatment failure or progress occurred mainly in granulomatous manifestations, mainly in granulomatous manifestations, especially in orbital granulomaespecially in orbital granuloma

3.3. Relapse rates were high (40%)Relapse rates were high (40%)


Churg-Strauss Syndrome: Description and Long-termChurg-Strauss Syndrome: Description and Long-termFollow-up of the 383 Patients Enrolled in the FVSG CohortFollow-up of the 383 Patients Enrolled in the FVSG Cohort


To describe the main characteristics and To describe the main characteristics and long-term outcomes of a large cohort of long-term outcomes of a large cohort of patients with well-characterized CSS patients with well-characterized CSS diagnosesdiagnoses


Characteristics and outcomes of CSS patients Characteristics and outcomes of CSS patients especially according to ANCA status and the especially according to ANCA status and the year of diagnosis (≤ or >1996, when the five-year of diagnosis (≤ or >1996, when the five-factor score (FFS) was devised) were factor score (FFS) was devised) were analyzedanalyzed

Pagnoux C, et al: Presented at EULAR 2011; Oral Presentation #OP0051.



383 patients (199 men, 184 women), diagnosed between March 1957 and 383 patients (199 men, 184 women), diagnosed between March 1957 and June 2009 [128 (33.4%) ≤1996], and followed for a mean ± SD of 67.1±62.8 June 2009 [128 (33.4%) ≤1996], and followed for a mean ± SD of 67.1±62.8 months. months.

Mean age at diagnosis: 50.3±15.7 yearsMean age at diagnosis: 50.3±15.7 years

Main manifestations:Main manifestations:

– Asthma (91.1% of the patients), with mean asthma duration of 111±130 Asthma (91.1% of the patients), with mean asthma duration of 111±130 months, months,

– Weight loss (49.4%), Weight loss (49.4%),

– Myalgias (38.9%), Myalgias (38.9%),

– Arthralgias (29.8%), Arthralgias (29.8%),

– ENT manifestations (48.0%),ENT manifestations (48.0%),

– Lung infiltrates (38.6%), Lung infiltrates (38.6%),

– Peripheral neuropathy (51.4%), Peripheral neuropathy (51.4%),

– Skin lesions (39.7%; mainly purpura), Skin lesions (39.7%; mainly purpura),

– Renal (21.7%), GI (23.2%) and/or cardiac (16.5%) involvement(s)Renal (21.7%), GI (23.2%) and/or cardiac (16.5%) involvement(s)




Mean eosinophil count was 7427±3763/mmMean eosinophil count was 7427±3763/mm33 and 106 (27.7%) and 106 (27.7%) patients were ANCApatients were ANCA++, mainly with antiMPO-ANCA (64% of , mainly with antiMPO-ANCA (64% of the ANCAthe ANCA++ patients). patients).

CSS was histologically proven for 162 (42.3%). CSS was histologically proven for 162 (42.3%).

ANCAANCA--, compared to ANCA, compared to ANCA++ patients, had significantly: patients, had significantly:

– More frequent cardiac manifestations (31.1% More frequent cardiac manifestations (31.1% vsvs. 17.9%; . 17.9%; p p = 0.01)= 0.01)

– Less frequent ENT manifestations, peripheral Less frequent ENT manifestations, peripheral neuropathy, renal involvement and lower BVAS (20.6 neuropathy, renal involvement and lower BVAS (20.6 vsvs. . 18.4; 18.4; p p = 0.04); they received cyclophosphamide less = 0.04); they received cyclophosphamide less frequently (43.3% frequently (43.3% vsvs. 57.6%; . 57.6%; p p = 0.01)= 0.01)




Multivariable analysis revealed as Multivariable analysis revealed as independent mortality risk factors:independent mortality risk factors:

– Cardiomyopathy (HR 3.23; 95 CI, 1.55-6.76)Cardiomyopathy (HR 3.23; 95 CI, 1.55-6.76)

– Age >65 years (HR 3.58; 95 CI, 1.60-8.02)Age >65 years (HR 3.58; 95 CI, 1.60-8.02)

– Diagnosis ≤1996 (HR=3.81; 95 CI, 1.57-9.21) Diagnosis ≤1996 (HR=3.81; 95 CI, 1.57-9.21)

– Creatinine >140 μmol/L (HR 18.6; 95 CI, Creatinine >140 μmol/L (HR 18.6; 95 CI, 4.43-78.4)4.43-78.4)


104

Last But Not Least, the OrphansLast But Not Least, the Orphans

Highlights of a EULAR Abstract Highlights of a EULAR Abstract Session held Friday, May 27Session held Friday, May 27

Summarized by Dr. Summarized by Dr. Nader KhalidiNader Khalidi

The Clinical Characteristics of Remitting Seronegative The Clinical Characteristics of Remitting Seronegative Symmetrical Synovitis with Pitting Edema (RS3PE) and the Symmetrical Synovitis with Pitting Edema (RS3PE) and the Complication with NeoplasiaComplication with Neoplasia

• Background: It was previously reported that.;Background: It was previously reported that.;

Serum levels of vascular endothelial growth Serum levels of vascular endothelial growth factor (VEGF) were markedly elevated in factor (VEGF) were markedly elevated in patients with RS3PEpatients with RS3PE

Serologic variables such as matrix Serologic variables such as matrix metalloproteinase 3 (MMP-3) and VEGF were metalloproteinase 3 (MMP-3) and VEGF were useful for monitoring the therapeutic efficacyuseful for monitoring the therapeutic efficacy

RS3PE has been reported to be complicated RS3PE has been reported to be complicated with solid tumorswith solid tumors

Origuchi T, et al: Presented at EULAR 2011; Oral Presentation #OP0267.



45 patients fulfilled the criteria of RS3PE45 patients fulfilled the criteria of RS3PE

– 9 patients were excluded owing to a lack of 9 patients were excluded owing to a lack of clinical data, and 35 patients with RS3PE were clinical data, and 35 patients with RS3PE were includedincluded

– Mean age was 78 years (59-89), and they Mean age was 78 years (59-89), and they included 17 men (48.6%) and 18 women (51.4%)included 17 men (48.6%) and 18 women (51.4%)

27 (77.1%) patients were diagnosed one week or 27 (77.1%) patients were diagnosed one week or more after onset, and 20 (57.1%) patients were more after onset, and 20 (57.1%) patients were diagnosed more than one month laterdiagnosed more than one month later

All patients had a good response to prednisoloneAll patients had a good response to prednisolone



• Results (Cont’d):Results (Cont’d):

In 9 patients (25.7%) RS3PE was complicated with In 9 patients (25.7%) RS3PE was complicated with neoplasianeoplasia

The serum levels of MMP-3 were high in 27 The serum levels of MMP-3 were high in 27 (77.1%) patients with RS3PE(77.1%) patients with RS3PE

Median MMP level in RS3PE patients complicated Median MMP level in RS3PE patients complicated with neoplasia (455.3 ng/mL) was significantly with neoplasia (455.3 ng/mL) was significantly higher than that in RS3PE patients without higher than that in RS3PE patients without neoplasia (149.0 ng/mL) (neoplasia (149.0 ng/mL) (pp < 0.05) < 0.05)

The mean serum level of VEGF was 1408.9 ng/mL The mean serum level of VEGF was 1408.9 ng/mL in 4 patients with RS3PE and 3008.3 ng/mL in 2 in 4 patients with RS3PE and 3008.3 ng/mL in 2 paraneoplastic RS3PE patientsparaneoplastic RS3PE patients




1.1. RS3PE is associated with a high-frequency RS3PE is associated with a high-frequency complication of neoplasiacomplication of neoplasia

2.2. Long time to make a diagnosis of RS3PELong time to make a diagnosis of RS3PE

3.3. RS3PE patients had high levels of MMP-3 and RS3PE patients had high levels of MMP-3 and VEGFVEGF

4.4. Early diagnosis of RS3PE is importantEarly diagnosis of RS3PE is important

5.5. MMP-3 and VEGF were useful for the diagnosis of MMP-3 and VEGF were useful for the diagnosis of paraneoplastic RS3PEparaneoplastic RS3PE


Dosing Requirement and Longer-term effects of Canakinumab for Dosing Requirement and Longer-term effects of Canakinumab for Treatment of All Phenotypes of Cryopyrin-associated Periodic Treatment of All Phenotypes of Cryopyrin-associated Periodic Syndrome (CAPS)Syndrome (CAPS)


Longer-term effects of interleukin-1beta blockade Longer-term effects of interleukin-1beta blockade in CAPS ascertained in an open label, phase-3 in CAPS ascertained in an open label, phase-3 study of canakinumab in the largest study cohort study of canakinumab in the largest study cohort to date of pediatric and adult patients with CAPS to date of pediatric and adult patients with CAPS phenotypes of all typesphenotypes of all types


Assess safety and tolerability of canakinumabAssess safety and tolerability of canakinumab

– Key efficacy assessments were complete Key efficacy assessments were complete clinical and serologic response (CR), clinical and serologic response (CR), maintenance of CR, and proportion of patients maintenance of CR, and proportion of patients requiring dose adjustmentsrequiring dose adjustments

Lachmann H, et al: Presented at EULAR 2011; Oral Presentation #OP0270.



Canakinumab was administered 8-weekly for up Canakinumab was administered 8-weekly for up to 2 years by s.c. injection, 150 mg to adults and 2 to 2 years by s.c. injection, 150 mg to adults and 2 mg/kg to patients ≤40 kgmg/kg to patients ≤40 kg

An increase in dose up to 600 mg or 8 mg/kg for An increase in dose up to 600 mg or 8 mg/kg for those ≤40 kg, and/or frequency of administration those ≤40 kg, and/or frequency of administration was allowed in patients who did not was allowed in patients who did not achieve/remain in CRachieve/remain in CR




166 patients (119 adult and 47 children) aged 3-91 166 patients (119 adult and 47 children) aged 3-91 years with a diagnosis of FCAS (n=30), MWS years with a diagnosis of FCAS (n=30), MWS (n=103), NOMID/CINCA (n=32) were treated(n=103), NOMID/CINCA (n=32) were treated

A greater proportion of children and patients with A greater proportion of children and patients with NOMID/CINCA required an adjustment of dose NOMID/CINCA required an adjustment of dose and frequency compared to adults or those with and frequency compared to adults or those with other phenotypesother phenotypes

Higher doses were required in children vs. adults Higher doses were required in children vs. adults and in NOMID/CINCA vs. other phenotypesand in NOMID/CINCA vs. other phenotypes



Phenotype(>40 kg / ≤ 40 kg)

Mean dose, mg Adjustments, n (%)

> 40 kg ≤ 40 kgDose or

frequencyDose Frequency

FCAS (27/3) 188.9 2.7 5 (16.6) 5 (16.6) 0

MWS (90/13) 199.8 5.5 20 (19.4) 17 (16.5) 11 (10.7)

NOMID / CINCA (19/13)

228.9 5.8 15 (46.9) 14 (43.8) 8 (25.0)

Age group

Total (166) 40 (24.1) 36 (21.7) 19 (11.4)

Adults (119) 23 (19.3) 20 (16.8) 8 (6.7)

Pediatrics (47) 17 (36.2) 16 (34.0) 11 (23.4)

FCAS = Familial cold auto-inflammatory syndromeMWS= Muckle Wells syndromeNOMID= Neonatal Onset Multisystem Inflammatory diseaseCINCA= Chronic Infantile Neurological, Cutaneous and Articular Syndrome. Lachmann H, et al: Presented at EULAR 2011; Oral Presentation #OP0270.



Canakinumab administered every 8 weeks was Canakinumab administered every 8 weeks was well tolerated and provided substantial disease well tolerated and provided substantial disease control in adults and children with all phenotypes control in adults and children with all phenotypes of CAPSof CAPS

Increased doses of canakinumab were efficacious Increased doses of canakinumab were efficacious in younger patients and those with more severe in younger patients and those with more severe CAPS disease without evidence of increased AE CAPS disease without evidence of increased AE ratesrates


Rituximab as a Therapeutic Tool in Severe Mixed Rituximab as a Therapeutic Tool in Severe Mixed Cryoglobulinemia: A Long-term Study on 22 PatientsCryoglobulinemia: A Long-term Study on 22 Patients


Type II mixed cryoglobulinemia (MC) is a systemic Type II mixed cryoglobulinemia (MC) is a systemic vasculitis sustained by proliferation of oligoclonal cells, vasculitis sustained by proliferation of oligoclonal cells, associated in most cases with hepatitis C virus (HCV) associated in most cases with hepatitis C virus (HCV) infectioninfection

Several studies suggest that clinical remission can be Several studies suggest that clinical remission can be achieved by human/mouse chimeric monoclonal antibody achieved by human/mouse chimeric monoclonal antibody that specifically reacts with the CD20 antigen (Rituximab)that specifically reacts with the CD20 antigen (Rituximab)

However, data on the long term effects of Rituximab, However, data on the long term effects of Rituximab, especially when administered alone are lackingespecially when administered alone are lacking

• Objective: Objective:

Evaluate the response by assessing the changes in clinical Evaluate the response by assessing the changes in clinical signs, symptoms, and laboratory parameters after rituximab signs, symptoms, and laboratory parameters after rituximab therapy in patients with Type II mixed cryoglobulinemiatherapy in patients with Type II mixed cryoglobulinemia

Roccatello D, et al: Presented at EULAR 2011; Oral Presentation #OP0273.



Patients were followed for 12-72 months (18 patients for 24 Patients were followed for 12-72 months (18 patients for 24 and 10 for 48 months)and 10 for 48 months)

22 patients, mean age 61.7 years (range 36-78), 21 with HCV 22 patients, mean age 61.7 years (range 36-78), 21 with HCV infection genotype 2a2c (7 cases), 1b (11 cases) and 3 (3 infection genotype 2a2c (7 cases), 1b (11 cases) and 3 (3 cases) and symptomatic type II MC with systemic cases) and symptomatic type II MC with systemic manifestationsmanifestations

– Severe renal involvement in 12 cases (11 biopsy-proven, Severe renal involvement in 12 cases (11 biopsy-proven, having diffuse membrano-proliferative having diffuse membrano-proliferative glomerulonephritis (10 patients) or renal vasculitis) large glomerulonephritis (10 patients) or renal vasculitis) large necrotizing ulcers (9), severe polyneuropathy (13)necrotizing ulcers (9), severe polyneuropathy (13)

– Considered eligible for rituximab treatment because of Considered eligible for rituximab treatment because of resistance (6 cases) or intolerance (6 cases) to resistance (6 cases) or intolerance (6 cases) to conventional therapy or important bone marrow conventional therapy or important bone marrow infiltration (5)infiltration (5)



• Methods (Cont'd) Methods (Cont'd)

5 patients were given Rituximab as a front-line therapy: 375 5 patients were given Rituximab as a front-line therapy: 375 mg/mmg/m22 i.v. on days 1, 8, 15, and 22 i.v. on days 1, 8, 15, and 22

2 more doses were administered 1 and 2 months later2 more doses were administered 1 and 2 months later

No other immunosuppressive drugs were addedNo other immunosuppressive drugs were added

Further infusions were given to 13 patientsFurther infusions were given to 13 patients

– 8 received a re-induction (2 doses in 2 weeks plus 1 8 received a re-induction (2 doses in 2 weeks plus 1 monthly infusion for 2 months) after 12-51 monthsmonthly infusion for 2 months) after 12-51 months

– 5 were allocated in a maintenance protocol for 1 year 5 were allocated in a maintenance protocol for 1 year after induction therapy (1 infusion at 3 months interval).after induction therapy (1 infusion at 3 months interval).




Levels of proteinuria, ESR, cryocrit, rheumatoid factor, and Levels of proteinuria, ESR, cryocrit, rheumatoid factor, and IgM significantly decreased at 6, 12, 18 and 24 months (IgM significantly decreased at 6, 12, 18 and 24 months (p p < < 0.01)0.01)

HCV viral load did not increase during the entire HCV viral load did not increase during the entire observation period. Bone marrow abnormalities were found observation period. Bone marrow abnormalities were found to reverse to normal in all the 5 re-examined patientsto reverse to normal in all the 5 re-examined patients

Improvement of polyneuropathy was documented by a Improvement of polyneuropathy was documented by a significant increase of the mean motor amplitude CMAP (significant increase of the mean motor amplitude CMAP (p p < < 0.02) and motor conduction velocity (0.02) and motor conduction velocity (p p < 0.05) 12 months < 0.05) 12 months after rituximab therapyafter rituximab therapy

Constitutional symptoms disappeared or amelioratedConstitutional symptoms disappeared or ameliorated

No acute or delayed side effects were seenNo acute or delayed side effects were seen




Based on this experience and a number of reports Based on this experience and a number of reports published in the last 5 years, Rituximab appears published in the last 5 years, Rituximab appears to be a safe and effective therapeutic option in to be a safe and effective therapeutic option in patients with HCV-associated MC severe systemic patients with HCV-associated MC severe systemic vasculitisvasculitis


119

Psychiatric Disease inPsychiatric Disease inRheumatology PracticeRheumatology Practice

Highlights of a EULAR Clinical Highlights of a EULAR Clinical Science Session held Wednesday, Science Session held Wednesday,

May 25May 25Summarized by Dr. Summarized by Dr. Liam MartinLiam Martin

Psychiatric Disease in Rheumatology Psychiatric Disease in Rheumatology Practice: Session OverviewPractice: Session Overview

• Series of talks with varying degrees of Series of talks with varying degrees of relevancerelevance

• Topics varied from evaluation of NPSLE to Topics varied from evaluation of NPSLE to Lyme brain disease to Psychiatric problems in Lyme brain disease to Psychiatric problems in FMFM

• Presenters from Italy, France, US, and ChinaPresenters from Italy, France, US, and China

Clinical Science session:Psychiatric Disease in Rheumatology Practice. EULAR 2011; Wed., May 25.

Neuropsychiatric SLE (NPSLE)Neuropsychiatric SLE (NPSLE)

• NPSLE is well recognizedNPSLE is well recognized

• Symptoms vary from H/A to cognitive Symptoms vary from H/A to cognitive dysfunction to strokedysfunction to stroke

• Can be difficult to diagnoseCan be difficult to diagnose

• MRI not always helpfulMRI not always helpful

• However, Spect scan is of value in speaker’s However, Spect scan is of value in speaker’s experienceexperience

Castellino G: Presented at EULAR 2011; Presentation #SP0009.

NPSLE: Key PointsNPSLE: Key Points

• In moderate to severe diseaseIn moderate to severe disease

Spect scan is positive when MRI is negativeSpect scan is positive when MRI is negative

• Diffusion weighted technique is used to Diffusion weighted technique is used to distinguish old versus new lesionsdistinguish old versus new lesions

• Spect scanning can assess function of brain Spect scanning can assess function of brain tissuetissue

• ProblemsProblems

ExpensiveExpensive

Not standardizedNot standardized

Lack of availabilityLack of availability

Castellino G: Presented at EULAR 2011; Presentation #SP0009.

Psychiatric Evidence in Chronic Fatigue Psychiatric Evidence in Chronic Fatigue Syndrome and Fibromyalgia SyndromeSyndrome and Fibromyalgia Syndrome

• 1,000’s of papers on both FM and CFS1,000’s of papers on both FM and CFS

• None comparing psychiatric involvementNone comparing psychiatric involvement

• Both conditions have criteria which involve Both conditions have criteria which involve excluding other causes of symptomsexcluding other causes of symptoms

• Both conditions have certain similarities and Both conditions have certain similarities and differencesdifferences

Buchwald DS: Presented at EULAR 2011; Presentation #SP0010.


• Sex, race, symptoms and natural history: Sex, race, symptoms and natural history: similarsimilar

• Low employability, decreased function, high Low employability, decreased function, high health care costshealth care costs

• Emotional disorders; childhood abuse; and Emotional disorders; childhood abuse; and difficult doctor-patient relationship – some difficult doctor-patient relationship – some differencesdifferences

• HPA disorders and treatment – differentHPA disorders and treatment – different



• OverlapOverlap

24 -42% of FM have CFS24 -42% of FM have CFS

25 – 75% CFS have FM25 – 75% CFS have FM

• Comorbid psychiatric conditions in CFS and FMComorbid psychiatric conditions in CFS and FM

30 – 60% in referral centres30 – 60% in referral centres

Less in general practiceLess in general practice

• Depression most commonDepression most common

• Symptoms difficult to diagnoseSymptoms difficult to diagnose



• Management issues arise CFS and FMManagement issues arise CFS and FM

Dysfunctional beliefsDysfunctional beliefs

Over exertion cycleOver exertion cycle

Passive strategiesPassive strategies

• Complexities in managementComplexities in management

Diagnosis and cureDiagnosis and cure

Time is of the essenceTime is of the essence

Family and other source of support Family and other source of support



• ManagementManagement

ValidateValidate

Assess psychiatric / psychological issuesAssess psychiatric / psychological issues

Abuse issues occur more frequently in FMAbuse issues occur more frequently in FM

Address these issues if presentAddress these issues if present


Psychiatric Manifestations of Lyme DiseasePsychiatric Manifestations of Lyme Disease

• Neuroborreliosis – relatively more common in Neuroborreliosis – relatively more common in EuropeEurope

• Alsace region in France has most number of Alsace region in France has most number of cases in Europecases in Europe

• 3.3% of blood donors in region have positive 3.3% of blood donors in region have positive serology; 1% have symptomsserology; 1% have symptoms

Blanc F: Presented during Clinical Science session:Psychiatric Disease in Rheumatology Practice. EULAR 2011; Wed., May 25.


• Neuroborreliosis is difficult to diagnoseNeuroborreliosis is difficult to diagnose

• Symptoms includeSymptoms include

Meningeal / radiculopathy: 7th cranial nerveMeningeal / radiculopathy: 7th cranial nerve

MeningitisMeningitis

Transverse myelitisTransverse myelitis

EncephalopathyEncephalopathy

Optic neuritisOptic neuritis

• Ratio of serum Lyme Elisa / CSF Lyme Elisa Ratio of serum Lyme Elisa / CSF Lyme Elisa



• Depression most common psychiatric symptomDepression most common psychiatric symptom

• 2 cases presented of patients who presented 2 cases presented of patients who presented with no previous history of psychiatric diseasewith no previous history of psychiatric disease

• Both presented with paranoiaBoth presented with paranoia

• Unresponsive to anti-psychotic medsUnresponsive to anti-psychotic meds

• Lyme antibodies positive in bothLyme antibodies positive in both

• Symptoms cleared completely with ceftriaxoneSymptoms cleared completely with ceftriaxone



• 1 cases of patient who presented with cognitive 1 cases of patient who presented with cognitive dysfunctiondysfunction

• Negative investigations but positive Lyme Negative investigations but positive Lyme serologyserology

• Symptoms cleared completely with ceftriaxoneSymptoms cleared completely with ceftriaxone

• Still remains wellStill remains well



• Psychiatric involvement in Lyme disease is rarePsychiatric involvement in Lyme disease is rare

• Neurologic symptoms are more commonNeurologic symptoms are more common

• Hard to diagnoseHard to diagnose

• Serum / CSF antibody ratio may helpSerum / CSF antibody ratio may help

• Tetracyclines are helpful in treatmentTetracyclines are helpful in treatment


Neuropsychiatric involvement in SLE in Neuropsychiatric involvement in SLE in ChinaChina

• Report of SLE in Peking from 1990 – 2004 (Peking university Report of SLE in Peking from 1990 – 2004 (Peking university hospital)hospital)

• Poor prognosis in patients with widespread systemic disease Poor prognosis in patients with widespread systemic disease or NPSLEor NPSLE

• Steroid therapy helped improve prognosis but dose of steroid Steroid therapy helped improve prognosis but dose of steroid not studiednot studied

• Study performed on all NPSLE patients by CRA (n=128)Study performed on all NPSLE patients by CRA (n=128)

All patients were confusedAll patients were confused

32 years, mean age; SLEDAI: high scores32 years, mean age; SLEDAI: high scores

Patients with transverse myelopathy includedPatients with transverse myelopathy included

All patients treated cyclophosphamide i.v. monthly and All patients treated cyclophosphamide i.v. monthly and either 200 mg, 500 mg or 1 g weeklyeither 200 mg, 500 mg or 1 g weekly

Ye S: Presented at EULAR 2011; Presentation #SP0011.


• All patients improved at 4 weeks; no apparent All patients improved at 4 weeks; no apparent difference between dosesdifference between doses

• 6 with myelopathy still had cord problems6 with myelopathy still had cord problems

• Treated with rituximab – 4 improved over 6 Treated with rituximab – 4 improved over 6 months, able to move legsmonths, able to move legs

• Investigators measured P selectin, VCAM, IL8Investigators measured P selectin, VCAM, IL8

High before, reduced to normal after High before, reduced to normal after treatmenttreatment



• Found new antibodyFound new antibody

Alpha internexinAlpha internexin

56 Kd, neurofilament protein56 Kd, neurofilament protein


NPSLE responds to IV steroids and IV cycloNPSLE responds to IV steroids and IV cyclo

May take up to 4 weeks to see responseMay take up to 4 weeks to see response

Poorer outcome for full recovery if patient has Poorer outcome for full recovery if patient has flaccid limbsflaccid limbs


136

RA – Tight control:RA – Tight control:Theory and PracticeTheory and Practice

Highlights of a EULAR Clinical Highlights of a EULAR Clinical Science Session heldScience Session held

Thursday, May 26Thursday, May 26Summarized by Dr. Summarized by Dr. Liam MartinLiam Martin

Tight Control: Overview of SessionTight Control: Overview of Session

• These talks focused on the new way of These talks focused on the new way of managing RAmanaging RA

Tight controlTight control

Treat to Target (T2T)Treat to Target (T2T)

• There were MANY talks which focused on this There were MANY talks which focused on this areaarea

• The EULAR guidelines were mentioned The EULAR guidelines were mentioned constantly regarding the ideal management of constantly regarding the ideal management of RARA

Clinical Science session:RA – Tight control: Theory and Practice. EULAR 2011; Wed., May 25.

Tight Control: The MASCOT StudyTight Control: The MASCOT Study

• Step-up design, published in 2007, trial Step-up design, published in 2007, trial commenced in 1999commenced in 1999

• Patients recruited from clinical practices in Patients recruited from clinical practices in ScotlandScotland

• 687 patients recruited – 552 completed 6 687 patients recruited – 552 completed 6 monthsmonths

• SSZ first drug; MTX added or substitutedSSZ first drug; MTX added or substituted

• Overall response was modest – was not aiming Overall response was modest – was not aiming for remissionfor remission

Porter D: Presented at EULAR 2011; Presentation #SP0044.

Tight Control: TICORATight Control: TICORA

• Step-up design; T2T; blinded assessmentStep-up design; T2T; blinded assessment

• Reviewed every month; Tx changed if DAS not Reviewed every month; Tx changed if DAS not 2.4 or less2.4 or less

• Remission in 65%; EULAR good response in Remission in 65%; EULAR good response in 80%; less X-ray damaged in tight control80%; less X-ray damaged in tight control

• Steroids used freely - ? Role in maintaining Steroids used freely - ? Role in maintaining controlcontrol


Tight Control: TEAR (UK and US)Tight Control: TEAR (UK and US)

• Triple therapy versus step-up therapyTriple therapy versus step-up therapy

• UK – monthly visits; tight control; T2TUK – monthly visits; tight control; T2T

• US – MTX to ETN/MTX versus triple US – MTX to ETN/MTX versus triple therapytherapy Both worked; Both worked;

Group not responding to triple therapy were Group not responding to triple therapy were switched to ETN/MTX; no increase in X-ray switched to ETN/MTX; no increase in X-ray damage in this groupdamage in this group

• EULAR guidelines – Add biologic if one EULAR guidelines – Add biologic if one DMARD not helpful – no dataDMARD not helpful – no data


Tight Control: SWEFOTTight Control: SWEFOT

• Step-up studyStep-up study

MTX for 3 months; 30% DAS good or MTX for 3 months; 30% DAS good or remissionremission

– Non smoker, low DAS at initiationNon smoker, low DAS at initiation

If not, switch to MTX/IFX versus triple therapyIf not, switch to MTX/IFX versus triple therapy

At 12 months: At 12 months:

– MTX/IFX 60% good EULAR versus 45% in MTX/IFX 60% good EULAR versus 45% in triple therapytriple therapy

Bratt J: Presented at EULAR 2011; Presentation #SP0045.

Tight Control: SWEFOTTight Control: SWEFOT

• At 12 months: At 12 months: MTX/IFX 60% good EULAR versus 45% in 3 therapyMTX/IFX 60% good EULAR versus 45% in 3 therapy

• At 24 monthsAt 24 months MTX/IFX 43% good EULAR versus 33% in 3 therapyMTX/IFX 43% good EULAR versus 33% in 3 therapy Not good response at 12 months no change at 24 monthsNot good response at 12 months no change at 24 months

• X-ray changes in both but less in MTX/IFXX-ray changes in both but less in MTX/IFX

• Risk factors for poor response: High CRP and Risk factors for poor response: High CRP and erosions at baselineerosions at baseline

• MTX responders at 3 months: at 24 months 80% in MTX responders at 3 months: at 24 months 80% in remission but X-ray progression on Sharp scoreremission but X-ray progression on Sharp score

Bratt J: Presented at EULAR 2011; Presentation #SP0045.

Tight Control: CAMERATight Control: CAMERA

• Computer-assisted management in early Computer-assisted management in early RARA

• Two studies: 1 and 2Two studies: 1 and 2

• CAMERA - 2CAMERA - 2 ERA – treated with MTX (119) or MTX with ERA – treated with MTX (119) or MTX with

prednisone (117)prednisone (117) Monthly visitsMonthly visits X-ray: primary outcomeX-ray: primary outcome DAS28, HAQ, Remission: secondary outcomeDAS28, HAQ, Remission: secondary outcome

Bakker M: Presented at EULAR 2011; Presentation #OP0138.

Tight Control: CAMERATight Control: CAMERA

• CAMERA 2 ResultsCAMERA 2 Results

61 MTX and 72 MTX/pred - remission61 MTX and 72 MTX/pred - remission

34 dropped out in MTX, 32 MTX/pred –A/E34 dropped out in MTX, 32 MTX/pred –A/E

Add adalimumab if not in remission at 3 monthsAdd adalimumab if not in remission at 3 months

Erosions less in MTX/PredErosions less in MTX/Pred

• CAMERA 1: Conventional versus tight controlCAMERA 1: Conventional versus tight control

MTX is anchor drugMTX is anchor drug

Computer calculated DAS scores for intense Computer calculated DAS scores for intense group – DAS <3.2 was targetgroup – DAS <3.2 was target

MTX switched to S.C at 3 months if not DAS not MTX switched to S.C at 3 months if not DAS not <3.2<3.2

Bakker M: Presented at EULAR 2011; Presentation #OP0138.

145

Genomics, Genetics & Genomics, Genetics & EpigeneticsEpigenetics

Highlights of the EULAR Poster Highlights of the EULAR Poster Session held Thursday, May 26Session held Thursday, May 26

Summarized by Dr. Summarized by Dr. Wojciech OlszynskiWojciech Olszynski

Genomics in RA:Genomics in RA:Key Points from Selected PostersKey Points from Selected Posters

• Recent genome wide and candidate gene Recent genome wide and candidate gene association = identified >30 confirmed loci association = identified >30 confirmed loci susceptible to RAsusceptible to RA

• Role of HLA BRB1 early ?, impact on joint damage?Role of HLA BRB1 early ?, impact on joint damage?

• RA CCP and RF + mainly (Japanese cohort 424)RA CCP and RF + mainly (Japanese cohort 424)

• 20 found with single nucleotide polymorphism 20 found with single nucleotide polymorphism (SNP) in relation to disease severity, genetic factor (SNP) in relation to disease severity, genetic factor of joint destruction?of joint destruction?

• CD40 genetic risk factor for AID (SLE), part of TNF CD40 genetic risk factor for AID (SLE), part of TNF receptor. CD40 expression and contribution to receptor. CD40 expression and contribution to aberrant and cellular response in SLEaberrant and cellular response in SLE

Suzuki T, et al: Presented at EULAR 2011; Poster #THU0082.Vazgiourakis V, et al: Presented at EULAR 2011; Poster #THU0084.

The Occurrence of Anti-citrullinated The Occurrence of Anti-citrullinated Autoantibodies in RA Discordant Twin PairsAutoantibodies in RA Discordant Twin Pairs

• ACPA so far in diagnosis and prognosis – part ACPA so far in diagnosis and prognosis – part of pathogenesis as well?of pathogenesis as well?

• Testing mono and dizygotic twins (162 twins) Testing mono and dizygotic twins (162 twins) with RA self reported with RA self reported

• The presence of strongly positive CCP found in The presence of strongly positive CCP found in monozygotic twins – genes are regulating the monozygotic twins – genes are regulating the presence of CCP presence of CCP

Svendsen AJ, et al: Presented at EULAR 2011; Poster #THU0083.

Genomics in OA and RAGenomics in OA and RA

• OA and phenotype definition ???OA and phenotype definition ???

• Similarities of RA based on ACPA studies?Similarities of RA based on ACPA studies?

• Based on 3000 individuals. from Sweden, some Based on 3000 individuals. from Sweden, some overlap between ACPA + and –overlap between ACPA + and –

• Non major histocompatibility genetic factors Non major histocompatibility genetic factors different in RA positive and negative ACPAdifferent in RA positive and negative ACPA

Panoutsopoulous K, et al: Presented at EULAR 2011; Poster #THU0085.Källberg HJ, et al: Presented at EULAR 2011; Poster #THU0086.

Relation between Psoriatic Arthritis and Relation between Psoriatic Arthritis and Psoriasis VulgarisPsoriasis Vulgaris

• Using genome-wide association studies Using genome-wide association studies (GWAS) many similarities found in Ps V and (GWAS) many similarities found in Ps V and those are not confirmed in PsAthose are not confirmed in PsA

• Need for further studies in PsA using GWAS?Need for further studies in PsA using GWAS?

Bowes J, et al: Presented at EULAR 2011; Poster #THU0088.

150

Epigenetic Regulation of Epigenetic Regulation of InflammationInflammation


held Thursday, May 26held Thursday, May 26Summarized by Dr. Summarized by Dr. Wojciech OlszynskiWojciech Olszynski

Epigenetics of Inflammation: Key PointsEpigenetics of Inflammation: Key Points

• Bioenergy sensor Sirtiun 1 (Sirt 1) is an Bioenergy sensor Sirtiun 1 (Sirt 1) is an genetic representation involved in genetic representation involved in inflammatory checkpoint/expression in inflammatory checkpoint/expression in leading to atherosclerosis, sepsis?leading to atherosclerosis, sepsis?

• In obesity, atherosclerosis, diabetes – Sirt1 In obesity, atherosclerosis, diabetes – Sirt1 is low what may predispose to chronic is low what may predispose to chronic proinflammatory state and proinflammatory state and sepsissepsis

• Epigenetic modifications are fundamental Epigenetic modifications are fundamental events in pathogenesis of RA (number of events in pathogenesis of RA (number of processes responsible for pathogenesis)processes responsible for pathogenesis)

McCall C: Presented at EULAR 2011; Presentation #SP0103.Gay S: Presented at EULAR 2011; Presentation #SP0104.

152

OsteoporosisOsteoporosis

Highlights of the EULAR Abstract Highlights of the EULAR Abstract Session held Friday, May 27Session held Friday, May 27

Summarized by Dr. Summarized by Dr. Wojciech OlszynskiWojciech Olszynski

Denosumab Discontinuation and Bone Remodelling Denosumab Discontinuation and Bone Remodelling in Postmenopausal Women with Osteoporosisin Postmenopausal Women with Osteoporosis

• Denosumab effects are reversible after Denosumab effects are reversible after discontinuationdiscontinuation

• From previous studies, 15 patients evaluated From previous studies, 15 patients evaluated after 12-36 months (markers and biopsies)after 12-36 months (markers and biopsies)

• Histomorphic and biochemical data – confirmed Histomorphic and biochemical data – confirmed reversibility of denosumab effectsreversibility of denosumab effects

• Clinical implications ?Clinical implications ?

Brown J: Presented at EULAR 2011; Presentation #OP0197.

Role of RANKL in OsteoporosisRole of RANKL in Osteoporosis

• New anti-RANKL antibody tested in phase I New anti-RANKL antibody tested in phase I (ALX-0141)(ALX-0141)11

Prolonged inhibitory effect after single, low Prolonged inhibitory effect after single, low dosedose

Effect sustained after 120 days, plan to check Effect sustained after 120 days, plan to check in 9 monthsin 9 months

• Osteoprotegerin blocks RANKL-RANK activityOsteoprotegerin blocks RANKL-RANK activity22

Osteoprotegerin is reduced in first 5 years Osteoprotegerin is reduced in first 5 years after menopauseafter menopause

Potential role of osteoprotegerin in therapyPotential role of osteoprotegerin in therapy

1. Van Bockstaele F: Presented at EULAR 2011; Presentation #OP0198.2. Abaza N: Presented at EULAR 2011; Presentation #OP0202.

Prolonged Bisphosphonate Release After Prolonged Bisphosphonate Release After Treatment in Women with OsteoporosisTreatment in Women with Osteoporosis

• Urinary excretion of risedronate and Urinary excretion of risedronate and alendronate measured after discontinuation of alendronate measured after discontinuation of treatmenttreatment

• Residual trace of alendronate was detected Residual trace of alendronate was detected much longer than after risedronate (up to 19 much longer than after risedronate (up to 19 months for the first one)months for the first one)

• Clinical implications?Clinical implications?

Peris P: Presented at EULAR 2011; Presentation #OP0200.

Strontium Ranelate for Postmenopausal Strontium Ranelate for Postmenopausal OsteoporosisOsteoporosis

• Prolonged use of Strontium ranelate, not other Prolonged use of Strontium ranelate, not other form !!!form !!!

• Data confirmed good bone strength based on Data confirmed good bone strength based on results from biopsies (microarchitecture) and results from biopsies (microarchitecture) and BMDBMD

• Not available in Canada (mistakenly other forms Not available in Canada (mistakenly other forms of strontium advised)of strontium advised)

Felsenberg D: Presented at EULAR 2011; Presentation #OP0203.

Validity of Fracture Risk Instruments: Validity of Fracture Risk Instruments: Systematic ReviewSystematic Review

• All instruments that have been used for fracture All instruments that have been used for fracture risk assessment do not have enough sensitivity risk assessment do not have enough sensitivity and specificityand specificity

No proper validity, reliability and No proper validity, reliability and responsivenessresponsiveness

• Clinical implications !!!Clinical implications !!!

Martinez-Lopez JA: Presented at EULAR 2011; Presentation #OP0201.

Effect of Alcohol Consumption on Bone Effect of Alcohol Consumption on Bone Mineral DensityMineral Density

• Alcohol overuse (abuse) result in decreased Alcohol overuse (abuse) result in decreased BMDBMD

• Of ~500 pts tested, alcohol excess was Of ~500 pts tested, alcohol excess was correlated with decreased BMD of the spine but correlated with decreased BMD of the spine but not at the femoral necknot at the femoral neck

• CaMos is showing up to 4 drinks for men and CaMos is showing up to 4 drinks for men and two drinks for women – positive effecttwo drinks for women – positive effect

• QUESTION – what is too much?QUESTION – what is too much?

Thomas D: Presented at EULAR 2011; Presentation #OP0204.

159

Update in RAUpdate in RATherapeuticsTherapeutics

Highlights of Various EULARHighlights of Various EULARSessions held Thursday & Friday, Sessions held Thursday & Friday,

May 26 and 27May 26 and 27Summarized by Dr. Summarized by Dr. Anthony RussellAnthony Russell

Spleen Tyrosine Kinase Inhibition in RA: Spleen Tyrosine Kinase Inhibition in RA: FostamatinibFostamatinib

• Fostamatinib is an oral spleen tyrosine kinase Fostamatinib is an oral spleen tyrosine kinase inhibitor (Syk)inhibitor (Syk)

T ½ = 13 hoursT ½ = 13 hours

Efficacy previously demonstrated (phase II)Efficacy previously demonstrated (phase II)

– Mean ACR 72% w/ 100 mg b.i.d (vs. 32% for Mean ACR 72% w/ 100 mg b.i.d (vs. 32% for placebo)placebo)

– Significant difference vs. placebo at week 1Significant difference vs. placebo at week 1

– Serum IL-6, MMP-3 fell by 1 weekSerum IL-6, MMP-3 fell by 1 week

Weinblatt ME: Presented at EULAR 2011 during Clinical Science Session:Update in RA therapeutics: targeting intracellular signalling, Friday, May 27.

Spleen Tyrosine Kinase Inhibition in RA: Spleen Tyrosine Kinase Inhibition in RA: Fostamatinib Safety ObservationsFostamatinib Safety Observations

• For patients experiencing adverse events on For patients experiencing adverse events on fostamatinib 100 mg b.i.d., cutting the dose led fostamatinib 100 mg b.i.d., cutting the dose led to their resolutionto their resolution

• No lipid effects reportedNo lipid effects reported

Weinblatt ME: Presented at EULAR 2011 during Clinical Science Session:Update in RA therapeutics: targeting intracellular signalling, Friday, May 27.

Adverse Event of Interest

150 mg b.i.d. 100 mg b.i.d. Placebo

Diarrhea 45% 16% 13%

Neutropenia 30% 10% 0

Increase in BP 6% 6% 0

JAK Inhibition with Tofacitinib:JAK Inhibition with Tofacitinib:Evidence from Phase II & III TrialsEvidence from Phase II & III Trials

• Efficacy of tofacitinib in all reported trials to Efficacy of tofacitinib in all reported trials to date is significant vs. placebo (in 12-24 week date is significant vs. placebo (in 12-24 week trials)trials)

ACR 20: 58.7-70.5%ACR 20: 58.7-70.5%

ACR 50: consistent 44% rangeACR 50: consistent 44% range

ACR 70: 24.6-30.7%ACR 70: 24.6-30.7%

• Safety concerns:Safety concerns:

Infections were more common vs. controls Infections were more common vs. controls

Elevations of transaminase enzymes Elevations of transaminase enzymes

Increases in LDL cholesterolIncreases in LDL cholesterol

Kremer J, et al: Presented at EULAR 2011; Presentation #SP0117.

Oral JAK Inhibitor (Tofacitinib) for RAOral JAK Inhibitor (Tofacitinib) for RA

• NB: Name changed from tasocitinibNB: Name changed from tasocitinib

Also known as CP-690,550Also known as CP-690,550

• T ½ = 3 hoursT ½ = 3 hours

• Efficacy previously documented in RA with 5 Efficacy previously documented in RA with 5 mg and 10 mg b.i.d.mg and 10 mg b.i.d.

• New phase III study demonstrated efficacy on New phase III study demonstrated efficacy on patient-reported outcomespatient-reported outcomes

Strand V, et al: Presented at EULAR 2011; Presentation #OP0063.

Interleukin (IL)-17B in RAInterleukin (IL)-17B in RA

• IL-17 has 5 homologuesIL-17 has 5 homologues

• Expression of IL-17B is seen in fibroblast-like Expression of IL-17B is seen in fibroblast-like synoviocytes, induced by TNFsynoviocytes, induced by TNFαα

IL-17B + TNF IL-17B + TNF αα = ↑ IL-6, etc. = ↑ IL-6, etc.

Kouri V-P: Presented at EULAR 2011; Presentation #OP0218.

Interleukin (IL)-17A in RAInterleukin (IL)-17A in RA

• Phase II RCT (n=237) of secukinumab in RA patientsPhase II RCT (n=237) of secukinumab in RA patients

Secukinumab 25, 75, 150 and 300 mg vs. placebo Secukinumab 25, 75, 150 and 300 mg vs. placebo (s.c. once monthly)(s.c. once monthly)

Primary outcome: ACR 20 at 16 weeksPrimary outcome: ACR 20 at 16 weeks

By week 12, patients treated with 75, 150 and 300 By week 12, patients treated with 75, 150 and 300 mg achieved a clinically meaningful DAS28 mg achieved a clinically meaningful DAS28 reduction of >1.2 compared with those on placeboreduction of >1.2 compared with those on placebo

Overall efficacy was greater among those with ↑ Overall efficacy was greater among those with ↑ CRP at baselineCRP at baseline

Genovese M, et al: Presented at EULAR 2011; Poster #FRI0380.

25 mg 75 mg 150 mg 300 mg Placebo

ACR 20 (%) 35% 45% 45% 54% 36%

Effect of Abatacept on Circulating Dendritic Effect of Abatacept on Circulating Dendritic CellsCells

• Study in 36 RA patients with inadequate response to TNF inhibitorsStudy in 36 RA patients with inadequate response to TNF inhibitors

• Treated with abatacept + MTXTreated with abatacept + MTX

• Assessed by flow cytometry at 0, 3 and 6 monthsAssessed by flow cytometry at 0, 3 and 6 months

• Plasmacytoid dendritic cells ↑ at 3 and 6 months with treatment Plasmacytoid dendritic cells ↑ at 3 and 6 months with treatment

• Tregs slightly decreased at month 3Tregs slightly decreased at month 3

• No other significant changesNo other significant changes

Shipley E, et al: Presented at EULAR 2011; Poster #FRI0353.

Baseline RA patients Normals

T cells 1.11 2.16

CD4 0.54 1.0

CD8 0.27 0.54

T reg 0.033 0.051

M. Dendritic cells 6829 15003

P. Dendritic cells 4683 7605

All differences statistically significant except T reg

Abatacept + Traditional DMARDs Severely Impairs Humoral Abatacept + Traditional DMARDs Severely Impairs Humoral Response to H1N1 Vaccination in RA PatientsResponse to H1N1 Vaccination in RA Patients

• Investigators used "epidemic" H1N1 Investigators used "epidemic" H1N1 vaccination in RA patients and controlsvaccination in RA patients and controls

• Seroconversion (response) was defined as;Seroconversion (response) was defined as;

Increase of AbT Increase of AbT >> 4x if prevaccine titer >10 4x if prevaccine titer >10

AbT AbT >> 40 if prevaccination titers 40 if prevaccination titers < < 1010

Ribiero A, et al: Presented at EULAR 2011; Poster #FRI0342.

Abatacept (n=11)*

Methotrexate (n=33)

Healthy controls (n=33)

Seroconversion 0% 19/33 (58%) 21/33 (64%)

*6 abatacept patients were also receiving MTX

168

RA – Non-TNF BiologicsRA – Non-TNF Biologics

Highlights of the EULAR Abstract Highlights of the EULAR Abstract Session held Thursday, May 26Session held Thursday, May 26

Summarized by Dr. Summarized by Dr. Janet PopeJanet Pope

Non-TNF Biologics: Session OverviewNon-TNF Biologics: Session Overview

• Abatacept s.c. is equal to i.v., with very good response rates Abatacept s.c. is equal to i.v., with very good response rates in a large RCT (presented also at ACR) in a large RCT (presented also at ACR)

• Many of the treatments studied are of modest benefit and not Many of the treatments studied are of modest benefit and not ready for prime time (anti-BAFF, anti-lymphotoxin alpha, anti-ready for prime time (anti-BAFF, anti-lymphotoxin alpha, anti-CD20 [ofatumumab])CD20 [ofatumumab])

• The efficacy of tocilizumab alone seems very favorable to The efficacy of tocilizumab alone seems very favorable to tocilizumab with MTXtocilizumab with MTX

• A second look at exact lipid profiles in TCZA second look at exact lipid profiles in TCZ

Tocilizumab may have overall favorable changes in lipid Tocilizumab may have overall favorable changes in lipid profileprofile

• Tocilizumab may be effective in amyloid secondary to RA (10 Tocilizumab may be effective in amyloid secondary to RA (10 cases presented from Japan, rare in NA, Europe)cases presented from Japan, rare in NA, Europe)

Abstract Session: RA – Non-TNF biologics. EULAR 2011; Thurs., May 26.

A Large, Phase IIIb Non-inferiority Trial of Subcutaneous Abatacept Compared with Intravenous Abatacept, in Patients

with Rheumatoid Arthritis M Genovese1, A Covarrubias2, G Leon3, E Mysler4, M Keiserman5, R Valente6, P Nash7, JA Simon Campos8, W Porawska9, J Box10, C Legerton11, E Nasanov12,

P Durez13, R Aranda14, R Pappu14, I Delaet14, J Teng14, R Alten15

170

1Stanford University, Palo Alto, CA, US; 2Centro Medico De Las Americas, Merida, Yucatan, Mexico; 3Instituto De Ginecologia Y Reproduccion, Lima, Peru; 4Organización Médica de Investigación, Buenos Aires, Argentina;

5Pontificial Catholic University, School of Medicine, Porto Alegre, Brazil; 6Physician Research Collaboration, Lincoln, NE, US; 7University of Queensland, Brisbane, Australia; 8Centro De Especialidades Médicas, Merida,

Mexico; 9Poznanski Osrodek Medyczny ‘Novamed’, Poznan, Poland; 10The Arthritis Clinic & Carolina Bone & Joint, Charlotte, NC, US; 11Low Country Rheumatology, Charleston, SC, US; 12Institute of Rheumatology, Moscow,

Russia; 13Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; 14Bristol-Myers Squibb Co., Princeton, NJ, US; 15Schlosspark-Klinik,Charité, University Medicine Berlin, Department of Internal

Medicine II, Rheumatology, Berlin, Germany

171

ACQUIRE Study Design

• SC injections administered on Day 1 (with IV loading dose) and weekly thereafter• IV infusions administered on Day 1, 15 and 29, and monthly thereafter

†Patients who completed Month 6 could continue into the long-term extension where all patients received SC abatacept 125 mg/week plus MTX (data not shown); SJC=swollen joint count; TJC=tender joint count

SC abatacept 125 mg/week plus MTX (IV placebo)

n=736

n=721

IV abatacept ~10 mg/kg plus MTX (SC placebo)

Day 1

IV abatacept loading dose (Day 1)

Month 6Primary endpoint: Non-inferiority of SC versus IV abatacept by ACR 20Other endpoints: Efficacy, safety

and immunogenicity

Randomization (1:1)Stratification by body weight

SC abatacept 125 mg/week plus MTX†

Patients with active RA and an

inadequate response to MTX (≥3 months)

≥10 SJC, ≥12 TJC and CRP ≥ 0.8 mg/dL

172

ITT population PP populationSC abatacept +

MTX(n=736)

IV abatacept + MTX

(n=721)

SC abatacept + MTX

(n=696)

IV abatacept + MTX

(n=683)

Age, years 49.9 (13.2) 50.1 (12.6) 49.9 (13.0) 49.9 (12.7)

Gender, % female 84.4 80.4 84.2 80.4

Race, % Caucasian 74.7 74.5 74.1 73.9

Weight, kg 72.0 (18.0) 71.8 (17.6) 72.1 (18.1) 71.5 (17.5)

Quartile ≤59.4 kg, % 25.5 24.7 25.4 25.0

Quartile >59.4 to ≤69 kg,

%

24.5 27.0 24.4 27.2

Quartile >69 to ≤81.9 kg,

%

24.9 24.3 24.7 24.5

Quartile >81.9 kg, % 25.1 24.0 25.4 23.3

Disease duration, years 7.6 (8.1) 7.7 (7.8) 7.6 (8.0) 7.7 (7.9)

Duration ≤2 years, % 32.6 30.7 32.9 30.2

Duration >2 to ≤5 years,

%

21.1 20.8 20.7 21.2

Duration >5 to ≤10 years,

%

19.3 22.7 19.3 22.7

Duration >10 years, % 27.0 25.8 27.2 25.9

Baseline Demographics

Data are mean standard deviation, unless otherwise stated

ACR 20, 50 and 70 Responses Over 6 Months

173

SC=76.0%

IV=75.8%

SC=51.5%

IV=50.3%

SC=26.4%

IV=25.1%

Data exclude eight patients due to site non-compliance; PP population included all randomized and treated patients who received at least one dose of study medication, excluding patients with a protocol deviation; Patients who discontinued were considered non-responders; Error bars represent 95% CI

ACR 20

ACR 50

ACR 70

0.5 1 3 4 652

Month

SC (n=693)

IV (n=678)

SC (n=693)

IV (n=678)

IV (n=678)

SC (n=693)

Pro

po

rtio

n o

f p

atie

nts

wit

h A

CR

20

, 50

or

70 r

esp

on

se (

%)

100

90

80

70

60

50

40

30

20

10

0

174

Overall Safety SummaryEvent, n (%) SC abatacept + MTX

(n=736)

IV abatacept + MTX

(n=721)

Deaths 2 (0.3) 5 (0.7)

SAEs 31 (4.2) 35 (4.9)

Discontinued due to SAEs 8 (1.1) 14 (1.9)

AEs 493 (67.0) 470 (65.2)

Discontinued due to AEs 15 (2.0) 25 (3.5)

Infections 234 (31.8) 221 (30.7)

Serious infections 5 (0.7) 10 (1.4)

Malignancies 3 (0.4) 5 (0.7)

Autoimmune events 7 (1.0) 6 (0.8)

Safety data are based on all patients who received at least one dose of abatacept and are reported up to 56 days post last study dose; Deaths occurring >56 days post last study dose are also included

• Safety profiles were similar across the different weight quartiles (≤59.4 kg, >59.4 to ≤69 kg, >69 to ≤81.9 kg and >81.9)

175

Subcutaneous Injection Site ReactionsEvent, n (%) SC abatacept

(n=736)

SC placebo*

(n=721)Total patients with subcutaneous injection site reactions

19 (2.6) 18 (2.5)

Pruritus 6 (0.8) 1 (0.1)

Erythema 5 (0.7) 1 (0.1)

Hematoma 4 (0.5) 4 (0.6)

Rash 2 (0.3) 1 (0.1)

Pain 1 (0.1) 4 (0.6)

Papule 1 (0.1) 3 (0.4)

Reaction 1 (0.1) 3 (0.4)

Urticaria 0 2 (0.3)

Other† 4 (0.5) 0

*Patients received IV abatacept; Data are based on all patients who received ≥1 dose of abatacept and are reported up to 56 days post last dose; Reactions were pre-specified; †Individual reactions not reported in more than one patient

Patients in the SC abatacept group also received IV placebo and patients in the IV abatacept group also received SC placebo

In the SC abatacept group, subcutaneous injection site reactions were mild in intensity in 18 out of 19 patients; 1 patient reported moderate reaction

Conclusions

The ACQUIRE trial has demonstrated that the efficacy and safety of weekly fixed dosing of SC abatacept, in patients with moderate-to-severe RA and an inadequate response to MTX, is comparable to that of IV abatacept

Efficacy benefits were observed irrespective of patient weight or disease duration

176

A Phase 2 Study of Monthly Subcutaneous LY2127399 (An A Phase 2 Study of Monthly Subcutaneous LY2127399 (An Anti-BAFF Monoclonal Antibody) in Patients with Active RAAnti-BAFF Monoclonal Antibody) in Patients with Active RA

Not totally impressive, high placebo response, mild reduction in CRP

*p < 0.05 compared to placebo; **p < 0.05 compared to placeboGenovese M: Presented at EULAR 2011; Presentation #OP0017.

Wk24Placebo

n=361mgn=30

3mgn=20

10mgn=15

30mgn=18

60mgn=13

120mgn=24

ACR20 Response (%) 44.4 40.0 45.0 46.7 61.1 53.8 70.8*

ACR50 Response (%) 22.2 10.0 10.0 33.3 11.1 7.7 37.5

ACR70 Response (%) 5.6 3.3 0.0 6.7 5.6 0.0 4.2

EULAR Response (Good/Moderate) %

57.1 64.3 52.6 57.1 76.5 58.3 82.6*

Mean Change in DAS28 (n)-1.448(n=35)

-1.539(n=28)

-1.026(n=19)

-1.678(n=14)

-1.536(n=17)

-1.642(n=12)

-1.915**(n=23)

Median Change in CRP -30.27 19.57 4.26 -13.82 -50.53 -44.23 -31.80

Median Change in ESR -9.19 -28.68 -9.58 -4.76 -22.02 -34.38 -32.39

Anti-Lymphotoxin-alpha Monoclonal Antibody: Results from a Phase I Anti-Lymphotoxin-alpha Monoclonal Antibody: Results from a Phase I Randomized, Placebo-controlled Clinical Trial in Patients with Active RARandomized, Placebo-controlled Clinical Trial in Patients with Active RA

Very small N, minimal change in DAS vs. placebo

Emu B: Presented at EULAR 2011; Presentation #OP0018.

Placebo(n=7)

MLTA3698A(n=16)

ACR20 (% patients) 57 75



DAS28-CRP (median reduction from baseline)

0.82 1.22

CRP (median % decrease from baseline)

8 28

Ofatumumab, A Fully Human Anti-CD20 MAb,Ofatumumab, A Fully Human Anti-CD20 MAb,in the Treatment of Biologic-naive RA Patientsin the Treatment of Biologic-naive RA Patients

Placebo Active anti-CD20

ACR 20 27 50

ACR 50 Not given Not given

ACR 70 Not given Not given

Moderate / Good EULAR Response 41 67

Rash/Urticaria <1% 21%/16%

RF positive and negative seemed to have same response, 24 weeks, n=219 analyzed of 260 patients, modest ACR 20, rash and urticaria frequent

Taylor P: Presented at EULAR 2011; Presentation #OP0019.

Tocilizumab + MTX Does Not Have Superior Clinical Efficacy to Tocilizumab + MTX Does Not Have Superior Clinical Efficacy to Tocilizumab Alone in RA Patients with Inadequate response to MTX Tocilizumab Alone in RA Patients with Inadequate response to MTX (ACT-RAY) Study(ACT-RAY) Study

Randomized to D/C Mtx or continue when starting TCZ 8mg/kg, non-inferiority study, results at 24 weeks look very similar EXCEPT for more in LDAS with MTX

Dougados M: Presented at EULAR 2011; Presentation #OP0020.

EndpointTCZ 8 mg/kg + MTX (n=277)

TCZ 8 mg/kg + PBO (n=276)

P

DAS28 remission rate (DAS28 <2.6) , % (n)

40.4 (112) 34.8 (96) 0.189

LDAS, % (n) (DAS28 ≤3.2) 61.7 (171) 51.5 (142) 0.028

EULAR good or moderate response, % (n)

89.5 (248) 85.8 (237) 0.190

SJC (mean change from baseline [SD])

-11.3 (8.07) -11.7 (9.46) 0.834

TJC (mean change from baseline [SD])

-17.2 (13.57) -17.0 (13.63) 0.945

ACR 20, % (n) 71.8 (199) 70.7 (195) 0.862

ACR 50, % (n) 45.1 (125) 40.9 (113) 0.436

ACR 70, % (n) 24.9 (69) 25.7 (71) 0.679

ACR 90, % (n) 5.8 (16) 5.1 (14) 0.837

MEASURE: Effects of Tocilizumab on MEASURE: Effects of Tocilizumab on Parameters of Lipids and InflammationParameters of Lipids and Inflammation

• TCZ induced quantitative changes in TCZ induced quantitative changes in lipoprotein profiles, altered HDL composition, lipoprotein profiles, altered HDL composition, and reduced the levels of inflammatory and and reduced the levels of inflammatory and prothrombotic markersprothrombotic markers

• These changes may favor improved CV risk-These changes may favor improved CV risk-benefit for RA patients treated with TCZ, benefit for RA patients treated with TCZ, although clinical correlates will be required for although clinical correlates will be required for validationvalidation

McInnes I: Presented at EULAR 2011; Presentation #OP0021.

182

RA – Abstracts of InterestRA – Abstracts of Interest

Highlights of EULAR Abstract and Highlights of EULAR Abstract and Poster Sessions heldPoster Sessions heldWednesday to Friday,Wednesday to Friday,

May 25 to 27May 25 to 27Summarized by Dr. Summarized by Dr. Janet PopeJanet Pope

Lipids in ERA: Manchester Cohort –Lipids in ERA: Manchester Cohort –Baseline CharacteristicsBaseline Characteristics

Al-Husain AZ: Presented at EULAR 2011; Poster #THU0265.

Variables Mean (SD) / N (%)

Age (years) 50.7 (19.7)

SBP (mmHg) 142 (22)

DBP (mmHg) 81 (10)

BMI (kg/m2) 26.7 (5)

CRP level (mg/L) 14.6 (20)

ACPA + 81 (27.4%)

RF + 115 (34.6%)

HAQ score 0.89 (0.7)

DAS 28 3.5 (1.2)

Females 223 (65.8%)

Smoker (current) 75 (23.9%)

Lipids in ERA: Manchester Cohort –Lipids in ERA: Manchester Cohort –ConclusionsConclusions

• In treatment-naive, early inflammatory arthritis In treatment-naive, early inflammatory arthritis patients, lipid profile remains within normal patients, lipid profile remains within normal limitslimits

• In contrast to other smaller studies, markers of In contrast to other smaller studies, markers of disease activity (CRP, DAS28) are negatively disease activity (CRP, DAS28) are negatively associated with TGassociated with TG

• In patients with early arthritis, inflammation In patients with early arthritis, inflammation mainly affects TGmainly affects TG

• Detailed study of TG subtypes may provide Detailed study of TG subtypes may provide insight to how inflammation alters CVD risk in insight to how inflammation alters CVD risk in RARA

Al-Husain AZ: Presented at EULAR 2011; Poster #THU0265.

PREVALENCE OF REMISSION IN EARLY RA PREVALENCE OF REMISSION IN EARLY RA -- A COMPARISON OF NEW A COMPARISON OF NEW REMISSION CRITERIA TO ESTABLISHED CRITERIAREMISSION CRITERIA TO ESTABLISHED CRITERIA

Obviously the proportion of ERA in remission will vary according to definition. The CATCH data were used for this study.

The new criteria from ACR/EULAR have the least in remission and the numbers are closest to SDAI and CDAI remission at 12 months but not as many at 6

months. The agreement is modest.

DAS28 <2.6 DAS28 <2.0SDAI </=3.3

CDAI </=2.8ACR/

EULAR

6 months 148 (45) 88 (27) 79 (24) 75 (23) 57 (17)

12 months 176 (53) 118 (36) 88 (27) 83 (25) 73 (22)

Kuriya B, et al: Presented at EULAR 2011; Poster #SAT0405.

Does RF Status Affect Response to Infliximab?Does RF Status Affect Response to Infliximab?Observational Cohort: RF negative status may be better

Pozdnyakova E, et al: Presented at EULAR 2011; Poster #THU0228

8

6

4

2

00 14 22 54

Weeks

RA, RF+

RA, RF-

p < 0.05 p < 0.05

Comparative Characteristics of the Answer (on EULAR) in Comparative Characteristics of the Answer (on EULAR) in Groups with RF+ and RF- RA Against Therapy by InfliximabGroups with RF+ and RF- RA Against Therapy by Infliximab

Pozdnyakova E, et al: Presented at EULAR 2011; Poster #THU0228

Validation of Power DopplerValidation of Power DopplerUltrasound in RA RemissionUltrasound in RA Remission

Absence of PD signal in 28 joints

Sensitivity Specificity LR + LR -

SDAI ≤ 3.354

(41.8 – 65.7)75.7

(59.9 – 86.3)2.22

(1.20 – 4.09)0.61

(0.44 – 083)

Boolean based

61.9(49.6 – 72.9)

67.6(51.5 – 80.4)

1.91(1.15 – 3.16)

0.56(0.39 – 0.81)

Absence of PD signal in 42 joints

Sensitivity Specificity LR + LR -

SDAI ≤ 3.356.1

(43.3 – 68.2)74.4

(59.8 – 85.1)2.19

(1.25 – 3.85)0.59

(0.42 – 0.83)

Boolean based

63.2(50.2 – 75.5)

65.1(50.2 – 77.6)

1.81(1.15 – 2.85)

0.57(0.38 – 0.84)

Most but not all patients with low SDAI had no power dopplerNot sure what the power doppler + means in clinical remission

Bertoli AM, et al: Presented at EULAR 2011; Poster #FRI0057

Validation of Power DopplerValidation of Power DopplerUltrasound in RA RemissionUltrasound in RA Remission

Most but not all patients with low SDAI had no power dopplerNot sure what the power doppler + means in clinical remission

Bertoli AM, et al: Presented at EULAR 2011; Poster #FRI0057

Patterns of Drug Use in a Large US Database Patterns of Drug Use in a Large US Database (California Medicaid)(California Medicaid)

311, EULAR 2011

TNF inhibitors at 20%, Coxibs increased then decreased, steroids decreasing

Wong AL, et al: Presented at EULAR 2011; Poster #THU0310.

Patterns of Drug Use in a Large US Patterns of Drug Use in a Large US Database (California Medicaid)Database (California Medicaid)

Patients CharacteristicsPatients CharacteristicsVariable Value

Age, mean (SD) 47.4 (11.2)

Female, n (%) 5,269 (81.5)

Race, n (%)

White 2,359 (36.5)

Hispanic 2,156 (33.4)

Black 784 (12.1)

Others 1,164 (18.0)

Medi-Cal &MediCare eligibility, n (%)

2,798 (43.3)

Comorbidities, mean (SD) 1.8 (2.0)

RA drug classes used, mean (SD) 2.6 (1.0)

Rheumatologist visits, mean (SD) 1.4 (7.7)

Predictors of RA Drugs UsedPredictors of RA Drugs UsedSignificant predictors OR (95% CI)

Age 0.99 (0.983 – 0.997)

Race

White 1.0

Hispanic 0.64 (0.55 – 0.78)

Black 0.47 (0.35 – 0.63)

Others 0.78 (0.64 – 0.96)

Medi-Cal &MediCare eligibility

1.20 (1.02 – 1.40)

# of RA drug fills* 2.66 (2.53 – 2.79)

History of RA length 1.33 (1.11 – 1.60)

# of comorbidities 0.90 (0.86 – 0.94)

*Biologics & DMARDsWong AL, et al: Presented at EULAR 2011; Poster #THU0310.

Predictors of RA Medication Use Predictors of RA Medication Use

• Whites received more DMARDsWhites received more DMARDs

• Drug access (MediCAL)Drug access (MediCAL)

• RA disease durationRA disease duration

• Fewer comorbiditiesFewer comorbidities


Patterns of RA Medication Use: ConclusionsPatterns of RA Medication Use: Conclusions

• Variations in RA med prescriptionsVariations in RA med prescriptions

• TNFi use 20% and seemingly increasingTNFi use 20% and seemingly increasing

• Steroids and Coxibs decreasingSteroids and Coxibs decreasing

• Access issues still exist (insurance plan, by Access issues still exist (insurance plan, by race /ethnicity)race /ethnicity)


Home Monitoring with Computerized RAPID-3Home Monitoring with Computerized RAPID-3Home monitoring shows flares and improvements

Appeared feasible (Pilot of RA and AS patients)Not sure of utility as you could ask a patient to call if flaring

Berthelot JM, et al: Presented at EULAR 2011; Poster #THU0349.

195

Late-breaking AbstractsLate-breaking Abstracts

Highlights of the EULAR Abstract Highlights of the EULAR Abstract Session held Friday, May 27Session held Friday, May 27

Summarized by Dr. Summarized by Dr. Majed KhraishiMajed Khraishi

Safety and Preliminary Evidence of Efficacy in a Phase I Clinical Trial of Safety and Preliminary Evidence of Efficacy in a Phase I Clinical Trial of Autologous Tolerising Dendritic Cells Exposed to Citrullinated Autologous Tolerising Dendritic Cells Exposed to Citrullinated Peptides (Rheumavax) in Patients with Rheumatoid ArthritisPeptides (Rheumavax) in Patients with Rheumatoid Arthritis


Bone marrow-derived dendritic cells modified Bone marrow-derived dendritic cells modified with the irreversible NF-kappaB inhibitor, Bay11-with the irreversible NF-kappaB inhibitor, Bay11-7082 (Bay-DCs), exposed to arthritogenic antigen, 7082 (Bay-DCs), exposed to arthritogenic antigen, transfer antigen-specific suppression of transfer antigen-specific suppression of inflammatory arthritis in mice, through induction inflammatory arthritis in mice, through induction of regulatory T cellsof regulatory T cells

Human peripheral blood (PB) monocyte-derived Human peripheral blood (PB) monocyte-derived DCs derived from healthy controls or RA patients DCs derived from healthy controls or RA patients similarly modified with Bay suppress T cell similarly modified with Bay suppress T cell responses responses in vitroin vitro

Thomas R, et al: Presented at EULAR 2011; Presentation #LB0004.

Safety and Preliminary Evidence of Efficacy in a Phase I Clinical Trial of Safety and Preliminary Evidence of Efficacy in a Phase I Clinical Trial of Autologous Tolerising Dendritic Cells Exposed to Citrullinated Autologous Tolerising Dendritic Cells Exposed to Citrullinated Peptides (Rheumavax) in Patients with Rheumatoid ArthritisPeptides (Rheumavax) in Patients with Rheumatoid Arthritis


To demonstrate that autologous PB DC immunotherapy can safely To demonstrate that autologous PB DC immunotherapy can safely modify the immune response to specific rheumatoid arthritis (RA) modify the immune response to specific rheumatoid arthritis (RA) autoantigensautoantigens


Phase I clinical trial of autologous Bay-DCs exposed to Phase I clinical trial of autologous Bay-DCs exposed to citrullinated peptide antigens (known as Rheumavax) in HLA-DR citrullinated peptide antigens (known as Rheumavax) in HLA-DR shared epitope (SE)+ anti-citrullinated peptide antibody (ACPA)+ shared epitope (SE)+ anti-citrullinated peptide antibody (ACPA)+ RA patientsRA patients

Early RA clinic: 11: 9:9 (PBO, 1m, 5M), 2-3 years duration, 1-3 Early RA clinic: 11: 9:9 (PBO, 1m, 5M), 2-3 years duration, 1-3 DMARDsDMARDs

• ResultsResults

AEs were all grade 1AEs were all grade 1

Only 2 patients did not respondOnly 2 patients did not respond

No flares in patients in remissionNo flares in patients in remission

Thomas R, et al: Presented at EULAR 2011; Presentation #LB0004.

Tofacitinib (CP-690,550) in Combination with Traditional DMARDS: Tofacitinib (CP-690,550) in Combination with Traditional DMARDS: Phase 3 Study in Patients with Active RA with Inadequate Response to Phase 3 Study in Patients with Active RA with Inadequate Response to DMARDSDMARDS


To compare efficacy and safety of tofacitinib vs placebo To compare efficacy and safety of tofacitinib vs placebo (PBO) in pts with active RA with inadequate response to ≥1 (PBO) in pts with active RA with inadequate response to ≥1 DMARDDMARD

• Methods: 12-month studyMethods: 12-month study

Patient on non-biologic background DMARDs were Patient on non-biologic background DMARDs were randomised (2:2:1) to tofacitinib 5 or 10 mg BID or PBO for randomised (2:2:1) to tofacitinib 5 or 10 mg BID or PBO for six monthssix months

At month 3 ‘non-responder’ PBO patients were advanced to At month 3 ‘non-responder’ PBO patients were advanced to tofacitinib 5 or 10 mg BIDtofacitinib 5 or 10 mg BID

At month 6, remaining PBO patients were advanced to At month 6, remaining PBO patients were advanced to tofacitinibtofacitinib

Primary endpoints: Primary endpoints: ACR20 and DAS28-4 (ESR) <2.6 ACR20 and DAS28-4 (ESR) <2.6 responses at month 6; change in HAQ-DI at month 3responses at month 6; change in HAQ-DI at month 3

Kremer J, et al: Presented at EULAR 2011; Presentation #LB0005.

Tofacitinib (CP-690,550) in Combination with Traditional DMARDS: Tofacitinib (CP-690,550) in Combination with Traditional DMARDS: Phase 3 Study in Patients with Active RA with Inadequate Response to Phase 3 Study in Patients with Active RA with Inadequate Response to DMARDSDMARDS

EfficacyACR20† (%)

N=777ACR50† (%)

N=777ACR70† (%)

N=777

∆HAQ-DI§

Mo 3N=731

DAS28-4 (ESR) <2.6†

(%) N=680

Mean ∆ DAS28-4

(ESR)‡ N=438

5 mg BID 52.7*** 33.8*** 13.2*** -0.46*** 11.0** -2.2***

10 mg BID 58.3*** 36.6*** 16.2*** -0.56*** 14.8*** -2.5***

PBO 31.2 12.7 3.2 -0.21 2.7 -1.6

Safety n (%)Months 0-3 Months 3-6 Months 0-6

AEs SAEs AEs SAEs D/C (AEs)

5 mg BID 166 (52.7) 9 (2.9) 121 (38.4) 5 (1.6) 13 (4.2)

10 mg BID 173 (54.4) 8 (2.5) 124 (39.0) 7 (2.2) 15 (4.7)

PBO 97 (61.0) 6 (3.8) 21 (25.9) 0 3 (1.9)

P→5 - - 16 (42.1) 0 2 (2.5)§

P→10 - - 18 (45.0) 0 3 (3.8)§

†Non-responder imputation; ‡Mixed-effect longitudinal linear model; §Months 3-6**p<0.001, ***p<0.0001 vs PBO Kremer J, et al: Presented at EULAR 2011; Presentation #LB0005.

Relative Mortality in People with Rheumatoid Arthritis Treated Relative Mortality in People with Rheumatoid Arthritis Treated Alternatively with Etanercept or DMARDs: Long-term Data from a Alternatively with Etanercept or DMARDs: Long-term Data from a Large, UK, Observational Cohort StudyLarge, UK, Observational Cohort Study

• Objective: To compare mortality in people treated with etanercept (ETN) with Objective: To compare mortality in people treated with etanercept (ETN) with those treated with DMARDsthose treated with DMARDs


The British Society of Rheumatology Biologics Register provided The British Society of Rheumatology Biologics Register provided anonymous, observational data for this analysis, characterizing ETN-anonymous, observational data for this analysis, characterizing ETN-treated patients and a DMARD-treated reference group (DMARD-RG)treated patients and a DMARD-treated reference group (DMARD-RG)

Patients are followed from baseline via consultant review and patient Patients are followed from baseline via consultant review and patient survey at 6-month intervals for three years and then annuallysurvey at 6-month intervals for three years and then annually

Subjects were defined as those with potential for five years follow-up, and a Subjects were defined as those with potential for five years follow-up, and a Disease Activity Score (DAS-28) >4.2Disease Activity Score (DAS-28) >4.2

Cases were defined as those recruited to the ETN groupCases were defined as those recruited to the ETN group

2 extreme, best and worst-case scenarios are reported2 extreme, best and worst-case scenarios are reported

– Scenario 1 censored cases 3-months after ETN discontinuationScenario 1 censored cases 3-months after ETN discontinuation

– Scenario 2 followed patients to the end of their recorded data in an Scenario 2 followed patients to the end of their recorded data in an intention to treat (ITT) analysisintention to treat (ITT) analysis

Emery P, et al: Presented at EULAR 2011; Presentation #LB0007.


• Results:Results: 3,431 people 3,431 people were treated with ETN (71.5%) and 1,365 were treated with ETN (71.5%) and 1,365

(28.5%) treated with DMARDs(28.5%) treated with DMARDs

Total follow-up (based on ITT) was 14,194 years in the ETN Total follow-up (based on ITT) was 14,194 years in the ETN group (mean 4.1; median 4.9), and 5,583 years in the group (mean 4.1; median 4.9), and 5,583 years in the DMARD-RG (mean 4.1; median 4.9)DMARD-RG (mean 4.1; median 4.9)

There were significant differences in baseline There were significant differences in baseline characteristics between the ETN and the DMARD-RGcharacteristics between the ETN and the DMARD-RG

– Mean age 55.4 versus 59.4, p<0.001Mean age 55.4 versus 59.4, p<0.001

– Duration of RA 13.6 versus 9.6 years, p<0.001Duration of RA 13.6 versus 9.6 years, p<0.001

– Mean HAQ 2.1 versus 1.7, p<0.001Mean HAQ 2.1 versus 1.7, p<0.001

– Mean DAS-28 6.7 versus 5.7, p<0.001)Mean DAS-28 6.7 versus 5.7, p<0.001)



• Results (Cont'd):Results (Cont'd): There were 186 deaths in the ETN group and 127 in the DMARD-RGThere were 186 deaths in the ETN group and 127 in the DMARD-RG

Crude mortality for the observed period was 13.1 deaths per 1,000 Crude mortality for the observed period was 13.1 deaths per 1,000 person years (PKPY) in the ETN group and 22.7 PKPY in the person years (PKPY) in the ETN group and 22.7 PKPY in the DMARD-RGDMARD-RG

Using the Cox models:Using the Cox models:

– Under scenario 1, HR = 0.64 (95%CI 0.46-0.90, p=0.009) Under scenario 1, HR = 0.64 (95%CI 0.46-0.90, p=0.009) following adjustment for RA duration, gender, age, non-RA following adjustment for RA duration, gender, age, non-RA drugs at baseline, smoking history, systolic blood pressure drugs at baseline, smoking history, systolic blood pressure (SBP) and baseline HAQ(SBP) and baseline HAQ

– In scenario 2, HR = 0.77 (95%CI 0.56-1.05, p=0.094) following In scenario 2, HR = 0.77 (95%CI 0.56-1.05, p=0.094) following adjustment for age, gender, smoking history, non-RA drugs at adjustment for age, gender, smoking history, non-RA drugs at baseline, SBP, BMI, baseline HAQ and baseline DAS-28baseline, SBP, BMI, baseline HAQ and baseline DAS-28

– The inclusion of time dependent variables did not substantially The inclusion of time dependent variables did not substantially affect the reported HRsaffect the reported HRs


Evaluation of Rilonacept for Prevention of Gout Flares During Initiation Evaluation of Rilonacept for Prevention of Gout Flares During Initiation of Uric Acid-Lowering Therapy: Results of a Phase 3, Randomized, of Uric Acid-Lowering Therapy: Results of a Phase 3, Randomized, Double-blind, Placebo-controlled Global TrialDouble-blind, Placebo-controlled Global Trial


Although attaining target serum levels is Although attaining target serum levels is critical to the long-term management of gout, critical to the long-term management of gout, uric acid-lowering therapy (ULT) can elicit uric acid-lowering therapy (ULT) can elicit gout attacks during the initial months of gout attacks during the initial months of therapytherapy


To evaluate the efficacy and safety of To evaluate the efficacy and safety of rilonacept (IL-1 Trap) for the prevention of rilonacept (IL-1 Trap) for the prevention of gout flares (GFs) during initiation of ULT with gout flares (GFs) during initiation of ULT with allopurinolallopurinol

Mitha E, et al: Presented at EULAR 2011; Presentation #LB0001.


• Subjects: Adults with gout, serum uric acid levels ≥446 Subjects: Adults with gout, serum uric acid levels ≥446 μmol/L, and self-reported history of ≥2 flares in the prior yearμmol/L, and self-reported history of ≥2 flares in the prior year

• Methods: 16-week trialMethods: 16-week trial

Patients were initiated on allopurinol 300 mg daily (lower Patients were initiated on allopurinol 300 mg daily (lower dose in those with renal dysfunction) with subsequent dose in those with renal dysfunction) with subsequent titration to achieve serum uric acid levels <357 μmol/L titration to achieve serum uric acid levels <357 μmol/L

Patients were randomized to receive weekly subcutaneous Patients were randomized to receive weekly subcutaneous injections of placebo, rilonacept 80 mg, or rilonacept 160 injections of placebo, rilonacept 80 mg, or rilonacept 160 mg with a double (loading) dose on Day 1mg with a double (loading) dose on Day 1

Flares were treated with NSAIDs and/or oral steroids while Flares were treated with NSAIDs and/or oral steroids while continuing study treatmentscontinuing study treatments

Primary endpoint: Number of flares per patientPrimary endpoint: Number of flares per patient

Safety and tolerability were also assessedSafety and tolerability were also assessed




248 patients were randomized248 patients were randomized

Baseline characteristics were similar among groups: 93% Baseline characteristics were similar among groups: 93% male, mean age 51 yearsmale, mean age 51 years


EndpointPlacebo (n=82)

Rilonacept80 mg (n=82)

Rilonacept 160 mg (n=84)

Number of flares 101 29 28

Mean # of flares 1.23 0.35 0.34

# of patients with flares 46 21 28

Serious adverse events 5 4 3

Gout is an Independent Risk Factor for Acute Gout is an Independent Risk Factor for Acute Myocardial Infarction in Young and Low-risk PatientsMyocardial Infarction in Young and Low-risk Patients


A high risk of acute myocardial infarction (AMI) A high risk of acute myocardial infarction (AMI) in gout patients has been observedin gout patients has been observed

There was a lack of evidence on the risk of AMI There was a lack of evidence on the risk of AMI in younger patients or those with low risk in younger patients or those with low risk profilesprofiles


To investigate the risk of AMI by comparing To investigate the risk of AMI by comparing rates of first admission for AMI among gout rates of first admission for AMI among gout and non-gout patients in a representative and non-gout patients in a representative sampling cohort of the general population in sampling cohort of the general population in TaiwanTaiwan

Kuo C-F, et al: Presented at EULAR 2011; Presentation #LB0002.

Gout is an Independent Risk Factor for Acute Gout is an Independent Risk Factor for Acute Myocardial Infarction in Young and Low-risk PatientsMyocardial Infarction in Young and Low-risk Patients


The primary data source was the Taiwan The primary data source was the Taiwan National Health Insurance databaseNational Health Insurance database

– Adults older than 20 years were included in Adults older than 20 years were included in the cohortthe cohort

– The cohort included 704,503 patients (men: The cohort included 704,503 patients (men: 360,432; women: 344,071)360,432; women: 344,071)

Multivariate Cox proportional hazards models Multivariate Cox proportional hazards models were used to evaluate the risk of AMI in gout were used to evaluate the risk of AMI in gout patientspatients


Gout is an Independent Risk Factor for Acute Myocardial Gout is an Independent Risk Factor for Acute Myocardial Infarction in Young and Low-risk PatientsInfarction in Young and Low-risk Patients


26,556 (3.8%) patients received a gout 26,556 (3.8%) patients received a gout diagnosis and treatment during 1996-1999diagnosis and treatment during 1996-1999

– 70.3% (n=18,674) were men70.3% (n=18,674) were men

– Mean age of patients was 42.7 yearsMean age of patients was 42.7 years

• Gout patients were significantly older Gout patients were significantly older than non-gout patients (55.4 vs. 42.0 than non-gout patients (55.4 vs. 42.0 years)years)

– Gout patients were significantly more likely Gout patients were significantly more likely to have diabetes and hypertension, with to have diabetes and hypertension, with ORs of 4.94 and 7.55, respectivelyORs of 4.94 and 7.55, respectively

Kuo C-F, et LB0002.


• Results (Cont'd):Results (Cont'd):

Total follow-up since January 2000: 5,622,532 Total follow-up since January 2000: 5,622,532 patient-yearspatient-years

During this period, 3718 (gout, n=463; non-During this period, 3718 (gout, n=463; non-gout, n=3255) patients were hospitalized due gout, n=3255) patients were hospitalized due to AMI, 299 (gout, n=35; non-gout, n=264) of to AMI, 299 (gout, n=35; non-gout, n=264) of whom suffered a fatal eventwhom suffered a fatal event

The incidence of AMI was 2.20 and 0.60 per The incidence of AMI was 2.20 and 0.60 per 1000 patient-years among gout and non-gout 1000 patient-years among gout and non-gout patients, respectively (log-rank test, p<0.001). patients, respectively (log-rank test, p<0.001).



• Results (Cont'd):Results (Cont'd):

After adjustment for age, sex, diabetes mellitus, After adjustment for age, sex, diabetes mellitus, hypertension, coronary heart disease, stroke, and hypertension, coronary heart disease, stroke, and end-stage renal disease, gout was associated end-stage renal disease, gout was associated with all-AMI (hazard ratio [HR], 1.23) and non-fatal with all-AMI (hazard ratio [HR], 1.23) and non-fatal AMI (HR, 1.26)AMI (HR, 1.26)

In patients without cardiovascular risk factors, In patients without cardiovascular risk factors, gout was associated with all-AMI (HR, 1.84); and gout was associated with all-AMI (HR, 1.84); and non-fatal AMI (HR, 1.80); after adjustment for age non-fatal AMI (HR, 1.80); after adjustment for age and sex.and sex.

The HRs (95% CI) for AMI in patients aged 20–44, The HRs (95% CI) for AMI in patients aged 20–44, 45–59, and 60 years or older were 1.59 (1.12–2.24), 45–59, and 60 years or older were 1.59 (1.12–2.24), 1.24 (1.08–1.41), and 1.11 (0.94–1.32), respectively1.24 (1.08–1.41), and 1.11 (0.94–1.32), respectively


Documents

1 EULAR 2011 Medical Passport Highlights of EULAR 2011 London, United Kingdom June 2011