EULAR 2008 – 9th Annual European Congress of Rheumatology

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					EULAR 2008 – 9th Annual European
Congress of Rheumatology

AMGEN/Wyeth Ambassador Consultancy Meeting

Scientific Highlights: Clinical Relevance

June 11-14, 2008
Paris, France
                                    EULAR 2008 – SCIENTIFIC HIGHLIGHTS




Disclosure
• Please note that Amgen/Wyeth has provided the speaker
  with an honorarium and will reimburse the speaker for
  reasonable expenses related to this event.
• The opinions expressed are those of the speaker, and do
  not necessarily reflect the views of Amgen/Wyeth.
                                                              EULAR 2008 – SCIENTIFIC HIGHLIGHTS

       Etanercept (Enbrel® ) Approved
       Indications in Canada
       • Treatment of moderately to severely active rheumatoid arthritis (RA) in adults.
         Treatment is effective in reducing the signs and symptoms of RA, inducing major
         clinical response, inhibiting the progression of structural damage, and improving
         physical function. Enbrel® can be initiated in combination with methotrexate
         (MTX) in adult patients or used alone.
       • Reducing signs and symptoms of moderately to severely active polyarticular
         juvenile rheumatoid arthritis (JRA) in patients aged 4 to 17 years who have had
         an inadequate response to one or more DMARDs. Enbrel® has not been
         studied in children < 4 years of age.
       • Reducing signs and symptoms, inhibiting the progression of structural damage
         of active arthritis, and improving physical function in adult patients with psoriatic
         arthritis. Enbrel® can be used in combination with MTX in adult patients who do
         not respond adequately to MTX alone.
       • Reducing signs and symptoms of active ankylosing spondylitis.
       • Treatment of adult patients with chronic moderate to severe plaque psoriasis
         who are candidates for systemic therapy or phototherapy.
Source: Enbrel Product Monograph, January 2008.
                                        EULAR 2008 – SCIENTIFIC HIGHLIGHTS

EULAR 2008 Scientific Highlights
Program Contributors
• Chair and Program Consultant
  – Edward C. Keystone, MD, FRCP(C)
• Program Contributors:
  – Cory Baillie, MD, FRPC (C)
  – Louis Bessette, MD, FRCP(C)
  – Vivian Bykerk, MD, FRCP(C)
  – Nicole Fahlman, MD, FRCP(C)
  – Robert C. Offer, MD, FRCP(C)
  – Leo Picard, MD, FRCP(C)
  – Jean-Pierre Raynauld, MD, FRCP(C)
  – Andy Thompson, MD, FRCP (C)
  – Yves Troyanov, MD, FRCP(C)
  – John Watterson, MD, FRCP(C)
                                                          EULAR 2008 – SCIENTIFIC HIGHLIGHTS




Slide Set Overview
1. Prognosis/Early Rheumatoid Arthritis (ERA)                                   Slide 6

2. Diagnostic/Imaging in RA                                                     Slide 25

3. Co-morbidities in RA                                                         Slide 32

4. Conventional RA Treatments                                                   Slide 40

5. Current Anti-TNF Biologics in RA                                             Slide 44

6. Current Non-Anti-TNF Biologics in RA                                         Slide 52

7. Newly Emerging Treatments in RA                                              Slide 59

8. Special Topics                                                               Slide 66

9. Ankylosing Spondylitis (AS)                                                  Slide 75

10. Psoriatic Arthritis (PsA) and Juvenile Idiopathic Arthritis (JIA)           Slide 84
PROGNOSIS/ERA
                                                                   EULAR 2008 – SCIENTIFIC HIGHLIGHTS




Concepts in True Remission
• True Remission Requires:
  – No subclinical synovitis by sensitive imaging
  – No structural progression despite clinical and sensitive
    imaging remission
  – Persistent (> at least one year)
  – Implies prevention of “bad outcomes”
  – Should be able to withdraw therapy




       Emery, P & Aletaha D., presented at Symposium “Remisison Possible”, EULAR 2008 Congress, Paris, June 11, 2008.
                                                                    EULAR 2008 – SCIENTIFIC HIGHLIGHTS




Issues in Achieving Remission
• Early Treatment is key
• Intensive therapy approach results in better outcomes
• Treat to a disease state




        Emery, P & Aletaha D., presented at Symposium “Remisison Possible”, EULAR 2008 Congress, Paris, June 11, 2008.
                                                                    EULAR 2008 – SCIENTIFIC HIGHLIGHTS

Characteristics and Predictors for
Achieving DMARD-free Remission

  Characteristics & Predictors for DMARD-free                                      Hazard ratio
                   Remission                                                   (univariate analysis)
Negative Family history                                                                   1.80
Low CRP at baseline                                                                 1.01 per mg/L
Short duration of complaints before presentation                                   1.08 per month
Non-smoking                                                                               1.80
Absence of IgM rheumatoid factor                                                          5.90
Absence of Anti-CCP antibodies                                                            11.60
Absence of HLA shared epitope alleles                                                     2.10



        MuItivariate analysis revealed low CRP at baseline and absence of anti-CCP antibodies
                   are significant independent predictors for DMARD-free remission.



                              van der Woude D, et al. Ann Rheum Dis 2008;67(Suppl II):48 Abstract OP-0002 (EULAR 2008)
                                                                    EULAR 2008 – SCIENTIFIC HIGHLIGHTS

 SWEFOT Trial: Early RA (ERA) Patient -
 Outcomes in Initial MTX Responders
 • N=487 with ERA (symptom duration < 1 year) for SWEFOT trial
 • All started MTX with rapid dose escalation to 20 mg/week
 • After 3-4 months, 144 patients with DAS28<3.2 continued on MTX & did not enter controlled
   portion of SWEFOT trial

                Patient Outcomes for Initial MTX Responders (n=144)
Parameter                                                          Time Points
                                         6 months                  9 months                    12 months
DAS28 values (mean ± SEM)                2.4 ±0.09*              2.43 ±0.12*                 2.53 ±0.10*
% patients with DAS28 < 3.2                 87%*                      79%*                        75%*
% patients with DAS28 < 2.6                 61%*                      59%*                        60%*
*p<0.001, compared with all other patients in SWEFOT trial analyzed as one group,
including those intolerant to MTX

               ERA initial MTX good responders (DAS28<3.2) continue to show very good
                  clinical responses throughout the first year on MTX monotherapy.

                            van Vollenhoven RF, et al. Ann Rheum Dis 2008;67(Suppl II):62 Abstract OP-0043 (EULAR 2008)
                                                                     EULAR 2008 – SCIENTIFIC HIGHLIGHTS


SWEFOT Trial: Addition of DMARDs vs. anti-TNF Therapy
in ERA Patients who Failed Initial MTX Therapy

• Arm A: Sulfasalazine 1000 mg BID + hydroxychloroquine 400 mg QD (n=130)
• Arm B: Infliximab 3 mg/kg/infusion given at 0, 2, 6 weeks, then q 8 wks (n=128)
     EULAR Good Response at 12 Months                         ACR Responses at 12 Months
                                                                         *
      * (p<0.01 vs. Arm A)               *
                                                                             * (p<0.01 vs. Arm A)

                                                                                            *




                    Subsequent addition of anti-TNF to reasonable trial of MTX is
                     clinically superior than addition of conventional DMARDs.

                                 van Vollenhoven RF, et al. Ann Rheum Dis 2008;67(Suppl II): Abstract LB0001 (EULAR 2008)
                                                                            EULAR 2008 – SCIENTIFIC HIGHLIGHTS


     Drug-Free Remission after Treatment Discontinuation of
     Methotrexate in Patients with Undifferentiated Arthritis

     • DBPCT; N=110, patients with undifferentiated arthritis (UA) who had not progressed to RA
     • Treated with MTX 15 mg/wk to 30 mg/wk, or PBO, for 1 yr; aiming for DAS ≤ 2.4

                             Patient Outcomes for Patients not progressed to RA (n=60)

   26% (10/39) of patients who discontinued MTX were ACPA(+) vs. only 5% (1/21) for PBO

   46% (18/39) of patients who discontinued MTX achieved drug-free remission after 30 months vs. 19% (4/21)
   of PBO patients

    20% (2/10) of ACPA(+) patients who discontinued MTX achieved drug-free remission after 30 months vs. 55%
   (16/29) of ACPA(-) patients who discontinued MTX after 30 months


    Predictors of remission: ACPA(-) status (odds ratio 5.0, p=0.047)=; age >65 yr (odds ratio 33, p=0.027 vs. age
                    <40 yr); symptom duration < 6 months (odds ratio 8, p=0.085 vs. >12 months).


   Methotrexate discontinuation can be tried in ACPA(-) patients with undifferentiated arthritis without
    baseline radiographic damage, but should be continued in ACPA(+) patients, irrespective of DAS.


ACPA: anti-citrullinated peptide antibody
                                              Visser K, et al. Ann Rheum Dis 2008;67(Suppl II):61 Abstract OP-0040 (EULAR 2008)
                                                                              EULAR 2008 – SCIENTIFIC HIGHLIGHTS

Physician-Defined Remission in RA in the
Swedish RA Registry
• Patients with RA followed in Swedish RA registry; N=3,986 (27,266 patient
  visits); disease activity “none” indicated in 1,081 patients (5,041 patient visits)

                  Correlates of remission by physician‟s global assessment:
                     Score = 0, on physician‟s global assessment (PGA)
                                                                                Mean ± SEM*
 DAS28                                                                            2.14 ± 0.01
 Swollen joint count (SJC)                                                        0.31 ± 0.01
 Tender joint count (TJC)                                                         0.53 ± 0.03
 ESR (mm/h)                                                                      14.34 ± 0.18
 CRP (mg/L)                                                                       7.96 ± 0.12
 Patient global (1-100)                                                          19.00 ± 0.29
 Patient pain (1-100)                                                            18.04 ± 0.28
 HAQ-disability index                                                             0.52 ± 0.01
 *SEM = standard error of mean

   In this large dataset, remission as determined by the physician, via PGA, corresponds better to the
                  DAS28-based EULAR definition than to ACR clinical remission criteria.†
                                 †Pinals   RS, et al. Arthritis Rheum 1981;24:1308-1315.

                             van Vollenhoven RF, et al. Ann Rheum Dis 2008;67(Suppl II):92 Abstract OP-0140 (EULAR 2008)
                                                           EULAR 2008 – SCIENTIFIC HIGHLIGHTS


COMET- Combination of Methotrexate and Etanercept
in Active Early Rheumatoid Arthritis: Study Design
                       Double-Blind Randomized Clinical Trial

                                                                  etanercept + MTX (1a)
                 Etanercept* + MTX**
                 (n=274)
  Randomize
     (N=542)    * 50 mg OW as 2 x 25 mg lyophilized                     etanercept (1b)
                ** up to 20 mg/wk po by week 8



                                                                  etanercept + MTX (2a)
                 Placebo Etanercept + MTX**
                 (n=268)
                                                                           MTX (2b)
                                       Period 1
                                                      52 wks              Period 2           104 wks
Coprimary endpoints:
1) Proportion of patients with DAS28 remission (<2.6) at 52 weeks
2) Change in baseline in modified total Sharp score (mTSS) at 52 weeks

                                                          Emery P, et al. Lancet, 2008: e-Pub July 16, 2008.
                                                           EULAR 2008 – SCIENTIFIC HIGHLIGHTS
COMET- Combination of Methotrexate and Etanercept in Active
Early Rheumatoid Arthritis: Primary Endpoint - DAS28
Remission Over Time

                          MTX (n=263)
      60%
                          ETN + MTX (n=265)

                                      *     *
      40%
                                  *
                              *
                          *
      20%
                  *
              †


       0%
             0        4   8 12 16 20 24 28 32 36 40 44 48 52

                                      Time (Weeks)
         More patients in ETN + MTX (80.7%) vs. MTX (70.5%) completed 52 wks largely
        because of larger number of withdrawals due to lack of efficacy in MTX only arm.

                                                           Emery P, et al. Lancet, 2008: e-Pub July 16, 2008.
                                                                           EULAR 2008 – SCIENTIFIC HIGHLIGHTS

  COMET- Combination of Methotrexate and Etanercept in Active
  Early Rheumatoid Arthritis: DAS28 and DAS Remission and Low
  Disease Activity (LDA)

                                                                                                            *

                                    * p<0.001                                     *


                                                        *
Percent of patients




                            *




                                 1, 2                       1                         1, 2                  1


      DAS28 Remission=DAS28 <2.6; DAS Remission=DAS <1.6; DSA28 LDA=DAS28 3.2; DAS LDA=DAS <2.4

                                        1. Emery P, et al. Ann Rheum Dis 2008;67(Suppl II):50 Abstract OP-0008 (EULAR 2008)
                                        2. Emery P, et al. Lancet, 2008: e-Pub July 16, 2008
                                                                                      EULAR 2008 – SCIENTIFIC HIGHLIGHTS

COMET: Combination of Methotrexate and Etanercept in Active
Early Rheumatoid Arthritis: Primary Endpoint -Radiographic
Outcomes


                                                       ¶                         ¶
      Mean Δ from baseline (mTSS)




                                    ¶ MTX 7.5 mg po up to 20 mg/wk by 8 wks – both
                                    groups; ETN 50 mg OW as 2 x 25 mg sc injections




                                                                                                             †
                                                   *
                                                                                 *
                                               1                                        1              1,2


* p<0.001; † p<<0.01

                                              1. Emery P, et al. Ann Rheum Dis 2008;67(Suppl II):50 Abstract OP-0008 (EULAR 2008).
                                                                                 2. Emery P, et al. Lancet, 2008: e-Pub July 16, 2008.
                                                                                 EULAR 2008 – SCIENTIFIC HIGHLIGHTS

COMET: Combination of Methotrexate and Etanercept in Active
Early Rheumatoid Arthritis: Radiographic Non-progression at 52
Weeks
                                                     ¶                               ¶




                                                                ¶ MTX   7.5 mg po up to 20 mg/wk by 8 wks –
                                                                both groups; ETN 50 mg OW as 2 x 25 mg sc
     % of Patients radiographic non-progression




                                                                injections

                                                          *                                         *
                                                                * p<0.0001




                                                  mTSS definition of non-progression
                                                                                 1. Emery P, et al. Lancet, 2008: e-Pub July 16, 2008.
                                        EULAR 2008 – SCIENTIFIC HIGHLIGHTS



COMET: Combination of Methotrexate and Etanercept in Active
Early Rheumatoid Arthritis: ACR Responses at Week 52




                             *                                    * p<0.001


                                       *
Percent of patients (mITT)




                                                                               *




                                           1. Emery P, et al. Lancet, 2008: e-Pub July 16, 2008.
                                                                                       EULAR 2008 – SCIENTIFIC HIGHLIGHTS



COMET: Combination of Methotrexate and Etanercept in Active
Early Rheumatoid Arthritis: Secondary Endpoints



                                                            *
                                                                                          ¶                        ¶




                                                                  * p<0.001                                 *
 % of Patients




                                          n=263         n=265                             n=241        n=256

                                                                              3                                   1,2


                 ¶ MTX 7.5 mg po up to 20 mg/wk by 8 wks – both groups; ETN 50 mg OW as 2 x 25 mg sc injections


                                          1. Emery P, et al. Ann Rheum Dis 2008;67(Suppl II):50 Abstract OP-0008 (EULAR 2008).
                                          2. Emery P, et al. Lancet, 2008: e-Pub July 16, 2008.
                                          3. Breedveld F, et al. Ann Rheum Dis 2008;67(Suppl II):320 Abstract FRI0107 (EULAR 2008).
                                                                             EULAR 2008 – SCIENTIFIC HIGHLIGHTS



COMET: Combination of Methotrexate and Etanercept in Active
Early Rheumatoid Arthritis: Work Productivity



                                              ¶                                           ¶




                                                  * p=0.011; **p=0.081
  Days




                                              *
                                                                                                 **




         ¶ MTX 7.5 mg po up to 20 mg/wk by 8 wks – both groups; ETN 50 mg OW as 2 x 25 mg sc injections


         Early treatment with ETN + MTX suggests attenuation of work productivity loss.

                                                      1. Anis A, et al. Ann Rheum Dis 2008;67(Suppl II):50 Abstract OP-0096 (EULAR 2008).
                                                                           EULAR 2008 – SCIENTIFIC HIGHLIGHTS
COMET Sub-analysis: Patients Who are Non-Responders at
Week 12 Achieve Response at Week 24 and Sustain Response
Gain at Week 52

•   DBPCT; N=110, patients with undifferentiated arthritis (UA) who had not progressed to RA;

•   Treated with MTX 15 mg/wk to 30 mg/wk, or PBO, for 1 yr; aiming for DAS ≤ 2.4;

•   At 12 months, 60 patients had not progressed to RA; MTX was discontinued (irrespective of DAS); clinical outcomes
    in these 60 pts analyzed; Sharp/van der Heidje (SHS) progression assessed after 30 months.

                                                                               % (n/N) of Week 24
       Non-responder Status at            % (n/N) of Non-
                                                                               Improvers Who
       12 Wks from baseline               Responders at Week 12
                                                                               Sustained DAS28
             ETN + MTX                    who Responded at 24
                                                                               Response from Week
                N=265                     Weeks
                                                                               24-52

              DAS28 Remission                    DAS28 Remission                      DAS28 Remission
               71% (188/265)                       27% (50/188)                         66% (33/50)

                 DAS28 LDA                          DAS28 LDA                             DAS28 LDA
                56% (148/265)                       28% (42/148)                          69% (29/42)

         DAS28 EULAR Good/Mod.               DAS28 EULAR Good/Mod.               DAS28 EULAR Good/Mod.
              14% (36/265)                         53% (19/36)                         58% (11/19)

                6 months of ETN + MTX combination therapy may be a reasonable therapeutic
                    duration before contemplating changes in treatment in ERA patients.
                                     1. Breedveld F, et al. Ann Rheum Dis 2008;67(Suppl II):50 Abstract FRI0107 (EULAR 2008).
                                                                       EULAR 2008 – SCIENTIFIC HIGHLIGHTS
 COMET - Combination of Methotrexate and Etanercept in Active
 Early Rheumatoid Arthritis: Impact of early treatment on
 functional status



                                                                                MTX               MTX + ETN
                                                                              (N=241)              (N=256)

Improvement in mean HAQ score at Week 12                                       32.3%                 50.1%*
Week 52: Mean HAQ score                                                         0.92                  0.68*
Clinically meaningful improvement in HAQ score
                                                                               78.4%                 87.9%†
(≥0.22)
*p<0.001; † p<0.01; Baseline HAQ score = 1.6 for MTX group, 1.7 for ETN+MTX group.
Median MTX dosage was 19.6 mg/wk and 16.8 mg/wk in MTX and ETN+MTX groups, respectively.




Although high levels of functional impairment were observed at baseline, half of the patients were restored
   to normal function (HAQ ≤0.5 ) after early treatment with combination of etanercept and methotrexate.




                                        Moots et al. Ann Rheum Dis 2008;67(Suppl II):188 Abstract THU0164 (EULAR 2008)
                                                                                              EULAR 2008 – SCIENTIFIC HIGHLIGHTS
                           COMET - Combination of Methotrexate and Etanercept in Active
                           Early Rheumatoid Arthritis: Improvements in Patient Reported
                           Outcomes


                                                                                                                                      *

                                                        *p<0.05
Mean percent improvement




                                                        (mITT analysis, LOCF)
                                                                                                               *
                                               *                                        *




                           SF-36 PCS - Short Form-36 Physical Component Summary; SF-36 MCS - Short Form-36 Mental Component
                               Summary (MCS); Fatigue VAS; EQ-5D VAS - EuroQOL-5D VAS; EQ-5D Utility - EuroQOL-5D Utility



                                                           Durez P, et al. Ann Rheum Dis 2008;67(Suppl II):605 Abstract AB0300 (EULAR 2008)
DIAGNOSTIC IMAGING IN RA
                                         EULAR 2008 – SCIENTIFIC HIGHLIGHTS




Ultrasound (US) Assessment in RA : Why ?
• Low cost, good accessibility, ability to scan multiple joints
  in relatively short periods of time
• Allows for simultaneous imaging of bone and soft tissue
• Can detect bone erosions, increased blood flow, synovitis,
  tenosynovitis, and enthesopathy




                                        Wakefield RJ, et al, J Rheumatol. 2007;34(4):848-851
                                                                          EULAR 2008 – SCIENTIFIC HIGHLIGHTS

Ultrasound and Inflammation in RA:
General Imaging Differences in Synovitis




      Synovial Hypertrophy                                                     Power Doppler:
     (Grey Scale or B-Mode)                                                 Vascularisation = active
      Measures Thickness                                                        inflammation
 (PP – proximal phalanx; MC – middle phalanx)                          (Graded with semi-quantitative scale:
                                                                        0=no signal, 3 =extreme)

     Keystone EC. Imaging in Rheumatoid Arthritis. Rheumatoid Arthritis, National Grand Rounds, 2007, Volume 1, Issue 7.
                                                                     EULAR 2008 – SCIENTIFIC HIGHLIGHTS


  Ultrasonography in the Assessment of Clinical
  Remission in RA Patients
• N=71 RA patients in clinical remission on DMARDs or biologicals had US to detect presence of
  subclinical inflammation by Mode B or Power Doppler method
• Mean age, 51±14 yr, 69% female

                                                             Ultrasound (US) findings
Number of patients in clinical
                                              Mode B US - Synovial
remission by DAS28 or SDAI                                                          Power Doppler (PD)
                                                  Hypertrophy (SH)
definition
                                                 2/51 (4%) no SH                     33/51 (66%) no PD
DAS28< 2.6; n = 51/71 (72%)
                                                     detected                               signal
SDAI < 5; n = 38/71 (54%)                       2/38 (5.4%) no SH                    29/38 (78%) no PD
(Simplified Disease Activity Index)                  detected                               signal
• Many patients with physician judged remission had low levels of disease activity that can be
  detected by US
• Low levels of disease activity are better shown by PD than SH (Mode B-US)
• SDAI seems better than DAS28 to accurately define clinical remission
                                      Balsa A et al. Ann Rheum Dis 2008;67(Suppl II):161Abstract THU0082 (EULAR 2008).
                                                                      EULAR 2008 – SCIENTIFIC HIGHLIGHTS


  Monitoring Treatment Efficacy in RA by Measuring
  Inflammatory Lesions: MRI vs. Conventional Measures
      Relative Efficiency in Relation to TJC for all Outcome Measures at 3 Months


                                                              N= 36, Median Age 52.8,
                                                              81% ♀, disease duration 7.6 yrs


                                                     Value >1 implies outcome more efficient
                                                     than TJC in detecting change.




                                            Referent




MRI total inflammation score displayed superior responsiveness compared to conventional measures.

                        Haavardsholm EA et al. Ann Rheum Dis 2008;67(Suppl II):354 Abstract SAT0415 (EULAR 2008).
                                                                            EULAR 2008 – SCIENTIFIC HIGHLIGHTS


 Power Doppler Ultrasonography (PDUS) Assessment
 of Active Synovitis in Clinical Remission in RA

 • Gray-scale ultrasonography (US) and intrarticular power Doppler (PD) signal
   assessment in patients with early RA (ERA) (N=64) and with long-standing RA
   (LSRA) (N=28) that achieved clinical remission (DAS<1.6)
 • 39.1% of patients with ERA and all patients with LSRA were on anti-TNFs

                                                          No synovitis detected by PDUS
Remission criteria                                  ERA (N=64)                              LSRA (N=28)
DAS <1.6                                                70.3%                                     67.8%
ACR Remission*                                          66.5%                                     72.7%
*ACR remission criteria: ≥ 5 of the following present for at least 2 consecutive months: Morning stiffness  15
minutes; No fatigue; No joint pain; No joint tenderness or pain on motion; No soft tissue swelling in joints of tendon
sheaths; ESR (Westergren method)  30 mm/h for a female or 20 mm/h for a male.
(Ranganath VK, et al. Clin Exp Rheumatol 2006;24(Suppl 43):S14-S21)




A combined approach with clinical evaluation for remission and ultrasonographic assessment may
  be useful to identify the minimal disease activity and to avoid the progression of joint damage.

                                            Bosello S, et al. Ann Rheum Dis 2008;67(Suppl II):298 Abstract FRI0036 (EULAR 2008)
                                                                         EULAR 2008 – SCIENTIFIC HIGHLIGHTS


 Can Imaging Detected Synovitis in TNF-Blocker Induced Clinical
 Remission be Accurately Detected by Clinical Measures

 • RA patients (N=50) in clinical remission (DAS28 <2.6) induced by TNF blockers;
   median age 55 yr; disease duration 10 yr; median 12 months in clinical remission;
   68% RF+; ultrasound of dominant hand and wrist performed.


                Percentage of joints with absence of imaging detected synovitis
                              in DAS28 remission sub-categories

               DAS28 < 1.0               DAS28 1-1.49              DAS28 1.5-1.99               DAS28 2.0-2.6
              No. of joints (%)         No. of joints (%)          No. of joints (%)           No. of joints (%)

GS = 0*           15 (42.9%)                40 (35.7%)                 48 (45.7%)                  44 (44.9%)
PD = 0*           29 (82.9%)                89 (79.5%)                 87 (82.9%)                  79 (80.6%)

*Absence of imaging detected synovitis defined as both a gray scale (GS) and power doppler (PD) score of 0



    In TNF blocker induced clinical remission, 50% of patients have positive PD on ultrasound of a single
      hand. No clinical features or clinical remission scores indicated significant sub-clinical synovitis.

                                         Saleem B, et al. Ann Rheum Dis 2008;67(Suppl II):481 Abstract SAT0145 (EULAR 2008)
CO-MORBIDITIES IN RA
                                                                             EULAR 2008 – SCIENTIFIC HIGHLIGHTS


  Rheumatoid Arthritis: An Important and Independent
  Risk Factor for Incident Cardiovascular Disease (CVD)

  • CARRÉ study: 3-yr incident of CVD in prospective cohort of n=353 RA outpatients vs.
    Hoorn study: 3-yr incident of CVD in population-based cohort of n=1852


                      Cox Regression Hazard Analysis for CVD in Dutch RA Patients
                               Compared with Dutch General Population

                                                               Odds Ratio               95% CI                p-value

Model 1: Crude Analysis                                            2.08               1.35 – 3.20             p < 0.01

Model II: Adjusted for age and gender                              2.01               1.30 – 3.11             p < 0.01

Model III: Adjusted for CV risk factors*                           1.97               1.18 – 3.29             p = 0.01

* Blood pressure, anti-hypertensive agent use, total cholesterol, statin use, waist to hip ratio, smoking


            Risk of incident CVD in RA is significantly elevated compared to the general population,
                  even after adjustment for a higher prevalence of traditional CV risk factors.

                     RA itself should be considered an important, permanent, CV risk factor.

                                            Peters MJL et al. Ann Rheum Dis 2008;67(Suppl II):309 Abstract FRI0074 (EULAR 2008).
                                                                       EULAR 2008 – SCIENTIFIC HIGHLIGHTS


 Contribution of Traditional Risk Factors for Cardiovascular
 Disease (CVD) in the Co-Morbidity & Mortality of RA
• Study conducted in consecutive RA patients (N=1404) with symptoms < 2yr duration, not on DMARDs
• patients from 9 districts in England; clinical and lab assessments done yearly (since 1986)

                Risk Factor                        Predictive power for CVD,
                                                      Odds Ratio (95% CI)
        Hyperlipidemia                                          4.0 (1.9 – 8.4)
        Older age                                               3.1 (2.3 – 3.9)
        Diabetes                                                2.2 (1.3 – 3.6)
        Hypertension                                            2.1 (1.6 – 2.8)
        Steroids                                                1.8 (1.2 – 3.0)
        Male                                                    1.7 (1.3 – 2.1)
        Autoimmune thyroid                                      1.6 (1.1 – 2.6)
        disease
        Smoking                                                 1.3 (1.0 – 1.8)
         Traditional risk factors for cardiovascular disease are present at early stages of RA and
                           appear to be related to cardiovascular disease & death.

                                         Koduri G, et al. Ann Rheum Dis 2008;67(Suppl II):93 Abstract OP-0143 (EULAR 2008)
                                                                           EULAR 2008 – SCIENTIFIC HIGHLIGHTS

Disease Activity Predicts Cardiovascular
Co-Morbidity in Very Early RA
• Prospective consecutive early RA (mean
                                                  Predictive effect of disease related and CV risk factors on
  6.6 months) cohort from north Sweden            progression of cardiovascular disease (time from disease
  followed for 5 years; data collected at         onset to “first cardiovascular event”) in patients with RA.
  inclusion (T0) and 5 years (T5).
                                                  Variables                                  RR*                        p value
• N=671 (461 female, 210 male)                    Age at disease onset                       1.047/yr                   =0.001
• Mean age 54.8 ± 0.6 yr                          Male                                       0.373/f                    <0.04
                                                  AUC DAS28 (12 months)                      1.038                      <0.05
• 360 patients reached T5
                                                  AUC DAS28 (24 months)                      1.020                      <0.05
• 98.2% treated with DMARDs
                                                  Hypertension T0                            3.248/+                    <0.01
• 73.1% treated with corticosteroids              HDL                                        0.241/mmol/L               <0.05
                                                  Triglycerides                              1.851/mmol/L               <0.01
                                                  Coxibs                                     2.228/+                    <0.05
                                                  * RR: Relative risk = relative multiplicative effect of the variable on the hazard
                                                  function corresponding to a 1 unit change in the variable



              In patients with newly diagnosed RA , predictors of cardiovascular events
              were: disease activity over time, hypertension, lipids, coxibs, age and sex.


                                     Innala L, et al. Ann Rheum Dis 2008;67(Suppl II):169 Abstract THU0106 (EULAR 2008).
                                                                    EULAR 2008 – SCIENTIFIC HIGHLIGHTS
Cardiovascular Risk Among Patients with RA in CORRONA:
Comparing the Explanatory Value of Traditional Cardiovascular
Risk Factors with RA Factors

• CORRONA registry cohort of RA (N=10,870) followed for a median of 24 months.
• Information on cardiovascular risk factors (CVRF) and rheumatoid arthritis disease factors
  (RADF) drawn from baseline questionnaires.
• 75 MIs or strokes were observed during follow-up to give composite event rate of 3.27 per
  1000 patient-years

                    Relative Risk (RR) (multivariable Cox regression)

        Cardiovascular risk factors               Rheumatoid arthritis disease factors
                 (CVRF)                                        (RADF)

     Race – 1.26                             Subcutaneous nodules – 1.44
     BMI – 1.25                              HAQ-DI – 1.20
     Prior MI – 1.75
                                             Clinical disease activity index (CDAI) - 1.06
     Tobacco Use – 1.92

           RA disease factors appear to have a similar explanatory value in RA patients as
               do cardiovascular risk factors in explaining cardiovascular endpoints.


                                 Solomon DH, et al. Ann Rheum Dis 2008;67(Suppl II):482 Abstract SAT0148 (EULAR 2008)
                                                                        EULAR 2008 – SCIENTIFIC HIGHLIGHTS


 Prevalence and Predictive Factors of Co-morbidity
 in RA Patients Over 20 Years

 • Swedish (Lund) early RA cohort
 • 183 ERA patients from 1985-89
 • Mean age 51 yr
 • Mean duration symptoms 12
   months
 • 64% women
 • DMARDs and/or biologics used
 • Co-morbidities recorded at all
   visits




 >40% patients had one comorbid condition at onset of disease & >80% developed an additional one during
follow-up. This cohort found 1 predictor of future cardiovascular co-morbidity: higher age at diagnosis of RA.


                                  Kapetanovic M, et al. Ann Rheum Dis 2008;67(Suppl II):327 Abstract THU0109 (EULAR 2008).
                                                                      EULAR 2008 – SCIENTIFIC HIGHLIGHTS


A Systematic Review of the Effects of Anti-TNF
Agents on Lipid Profile
• 11 studies suitable: infliximab 9, adalimumab 1, all three TNFi 1
• 10/11 in RA, other study recruited RA, AS & PsA patients
• Total n=506
• DMARDs and corticosteroids used in all studies


 % Change from Baseline               Week 2                     Week 26                         Week 52

 Total Cholesterol (TC)                   5%                         7%                              4%
 HDL                                      4%                         7%                              -1%
 LDL                                      9%                         6%                              3%
 Triglycerides (TGL)                     10%                         6%                             15%*
                                                               *only one study reported TGL at week 52 – result may be skewed


                 Anti-TNFs increase the level of all lipid subsets from 2 weeks therapy
                initiation; LDL levels increase > HDL which tend to level by 52 weeks.


                                Rachapalli SM, et al. Ann Rheum Dis 2008;67(Suppl II):327 Abstract FRI0134 (EULAR 2008).
                                                                                 EULAR 2008 – SCIENTIFIC HIGHLIGHTS

   Anti-TNF Agents and Risk of Lymphoma
   Over 3 Years: RATIO Observatory
   • Prospective cohort from 490 clinical departments in France by RATIO group

                  38 cases of lymphoma in 3 years; 55% men; median age 63.5 yr
                                              (31 cases non-Hodgkin‟s lymphoma)
                   Last anti-TNF prior to lymphoma: IFX (n=18); ADA (n=13); ETN (n=7)
                                       (11 patients received more than 1 anti-TNF agent)


                           Median total anti-TNF treatment duration before lymphoma =
                                          106.7 wk (range 5.3 – 278.4 wk)
      Factors predictive of lymphoma (multivariate analysis):
                                                                                    Hazard Ratio (HR)
      Duration in mths between initiation 1st anti-TNF & lymphoma:                  0.99 (0.98 - 1.00); p = 0.009
      Using of Adalimumab vs. Etanercept:                                           6.74 (1.60 - 28.42); p = 0.009
      Using of Infliximab vs. Etanercept:                                           5.67 (1.36 – 23.76); p = 0.02

      Comparisons with General French Population:

                                                              Standardized Mortality Rate (SMR)
      Non-Hodgkin‟s Lymphoma in Anti-TNFs                            2.14 (1.51 – 3.04); p<0.0001
      Hodgkin‟s Lymphoma in Anti-TNFs                                5.05 (2.41 – 10.60); p<0.0001


Increased risk of lymphoma seems higher with monoclonal antibodies than soluble receptor anti-TNFs.

                                           Mariette X et al. Ann Rheum Dis 2008;67(Suppl II):323 Abstract FRI0116 (EULAR 2008).
CONVENTIONAL TREATMENTS IN RA
                                                                        EULAR 2008 – SCIENTIFIC HIGHLIGHTS


 Response of Elderly vs. Young RA Patients to
 MTX or MTX plus TNF-Inhibitors at 1 Year

                                                          Baseline (BL) to                 Baseline (BL) to
     Treatment           Quartile       Age (yr)        Endpoint (EP) SDAI *              Endpoint (EP) HAQ†
                                                          BL       EP - 1 Yr                BL     EP - 1 Yr
                             Q1           18-42             40.6            13.7            1.43             0.66
 MTX monotherapy             Q2           43-52             41.7            15.4            1.42             0.77
 N=438 (pooled from
   early RA trials)          Q3           53-61             44.5            16.9            1.45             0.76
                             Q4           62-82             46.6            14.8            1.69             0.78
                             Q1           18-42             40.7             8.4            1.41             0.41
MTX + TNF inhibitors
 N=794 (pooled from          Q2           43-52             40.7            12.8            1.43             0.60
IFX ASPIRE trial and         Q3           53-61             40.5             11.9           1.54             0.62
 ADA PREMIER trial)
                             Q4           62-82             42.2            10.3            1.56             0.63
* p <0.05 for methotrexate group only; † p<0.05 for both groups; *SDAI = Simplified Disease Activity Score;
†HAQ = Health Assessment Questionnaire


   Improvement of HAQ & inhibition of disease progression superior with anti-TNFs + MTX vs.
                                 MTX, independently of age.

                                     Koeller MD, et al. Ann Rheum Dis 2008;67(Suppl II):171 Abstract THU0113 (EULAR 2008).
                                                                                      EULAR 2008 – SCIENTIFIC HIGHLIGHTS
 Methotrexate plus other DMARDS vs methotrexate plus
 TNF-inhibitors in patients with early RA who have failed
 methotrexate monotherapy

 • NOR-DMARD register (Norway) 2787 RA patients
 • 99 patients met criteria of duration < 2yrs & had started and failed MTX
   monotherapy, then switched to either MTX+DMARD or MTX+TNF inhibitor
            Mean changes (SD) in composite of disease activity and response rates*
                                                  MTX + DMARD                      MTX + TNF inhibitor            p value
                                                     (N=60)                              (N=39)
DAS28                                                -1.03 (1.33)                      -1.87 (1.63)                0.011
SDAI                                                  -9.2 (13.9)                      -17.4 (15.0)                0.013
CDAI                                                  -8.6 (12.7)                      -16.0 (14.6)                0.012
EULAR good response (%)                                   18.4                            47.2                     0.004
SDAI major response (%)                                   16.7                            37.1                     0.034
CDAI major response                                       31.5                            54.1                     0.031
*After 6 months of therapy (LOCF for missing data)
SDAI - Simplified disease activity index; CDAI – clinical disease activity index


 Direct switch from MTX to MTX+TNF inhibitor appears to be more effective than switching to MTX+DMARD.

                                                        Lie E, et al. Ann Rheum Dis 2008;67(Suppl II):201 Abstract THU0204 (EULAR 2008)
                                                                     EULAR 2008 – SCIENTIFIC HIGHLIGHTS

Reporting of Disease Activity States
in Clinical Trials of Rheumatoid Arthritis
• Pooled data from the methotrexate arms of            Mean HAQ (left panel) and mean radiographic
  recent RA trials (ASPIRE, ERA, PREMIER,              progression (right panel) in ACR50 responders
  TEMPO) (N=629)                                          (N=352) who achieve REM, LDA or MDA
                                                                *p<0.0001 vs LDA,                   *p<0.008 vs
• Comparison of functional impairment and                       MDA                                 LDA, MDA
  radiographic progression in ACR50 and
  ACR70 responders who achieved remission
  (REM), low disease activity (LDA) or
  moderate disease activity (MDA) after 1 yr.




                                                                                                *
                                                                 *




     Functional and radiographic outcomes are different in patients depending on the disease activity
       category they reach, even if the same level of response (change from baseline) is achieved.


                                     Aletaha D, et al. Ann Rheum Dis 2008;67(Suppl II):426 Abstract FRI0458 (EULAR 2008)
CURRENT ANTI-TNF BIOLOGICS IN RA
                                                                         EULAR 2008 – SCIENTIFIC HIGHLIGHTS

    Risk of Solid Tumours in Patients Treated
    with Biologics: RABBIT Registry
    • Prospective cohort nested case-control study (German Biologics Register – RABBIT);
      excluded patients with prior malignancies

        N=5000 patients; follow-up time of 3 months – 6 years (mean: 2.4 years)
     69 patients developed a solid malignancy – 48 cases (70%) female
     Overall Incidence Rate: 5.8/1000 patient years (pt-yrs)
     1st Year Incident Rate: 4.8/1000 pt-yrs
     2nd Year Incident Rate: 6.2/1000 pt-yrs
     3rd Year Incident Rate: 5.8/1000 pt-yrs
     4th – 6th Year Incident Rate: 8.1/1000 py-yrs

     Most frequent cancer types:
     Lung – 13; Breast – 12; Skin – 9; Pancreas – 6; Reproductive organs (10)
     Cases & control had similar age, mean-follow-up and DAS28 at entry
     Exposure to Biologics: 40 cases vs. 38 controls (p=0.82)

No difference was found in incidence of solid malignancies in patients exposed or non-exposed to biologics.


                                     Strangfeld A, et al. Ann Rheum Dis 2008;67(Suppl II):332 Abstract FRI0143 (EULAR 2008).
                                                             EULAR 2008 – SCIENTIFIC HIGHLIGHTS

 Anti-TNF Therapy in RA and Cancer Risk:
 ARTIS Registry
 • National cohort of ERA & RA patients in Sweden between 1998-2006,
   N= 66 995
 • Swedish Biologics Register (ARTIS) identified 6403 patients started on
   anti-TNFs during 1998-2005

169 primary cancers following anti-TNF therapy
RR 0.94 (95% CI: 0.80 – 1.12) with anti-TNF treated vs. cancers that
occurred in RA pts without anti-TNF therapy (n=3746)
RR 1.04 (95% CI: 0.89 – 1.21) with anti-TNF compared with general
population
No trend with time from treatment start or with cumulative exposure to first
anti-TNF agent

        No increase in overall risk of cancer was observed with anti-TNF
         therapy since treatment start or during first 5 years of therapy.
                             Askling J, et al. Ann Rheum Dis 2008;67(Suppl II):52 Abstract OP-0013 (EULAR 2008).
                                                               EULAR 2008 – SCIENTIFIC HIGHLIGHTS

Meta-analysis of Etanercept for Risk of
Malignancy
• 9 RCTs, N=2244 for ETN (2484 pt-yrs), N=1072 controls (1051 pt-yrs)1
• Patient level data: 26 malignancies diagnosed in ETN vs. 7 cases in control group
  (most common = non-melanoma of skin)1
• Incidence rates:
   – ETN 10.46/1000 pt-yrs vs. control 6.66/1000 pt-yrs
• Hazard ratios: ETN vs. control
   – 1.84 (95% CI: 0.79 – 4.28); p=0.16
   – 1.87 (95% CI: 0.75 – 4.62); excluding 1st 42 days
   – 1.86 (95% CI: 0.62-5.59); excluding non-melanoma skin cancers
• Results not inconsistent from Bongartz et al. 2006 meta-analysis of RCTs for ADA
  & IFX: Hazard Ratio: 2.4 (95% CI: 1.2 – 5.6)2

     Etanercept associated with higher risk of malignancies vs. control but not
statistically significant; with small # of events cannot make definitive conclusions.

                           1. Bongartz T, et al. Ann Rheum Dis 2008;67(Suppl II):51 Abstract OP-0012 (EULAR 2008.
                           2. Bongartz T, et al. JAMA 2006;295:2275-2285.
                                                         EULAR 2008 – SCIENTIFIC HIGHLIGHTS

Occurrence of Dose Escalation During First
Year Anti-TNF Treatment: DART Study
                              p < 0.001                         Starting doses (all 1st treatments):
                                                                1. ETN 25 mg BIW or 50 mg OW
                                                                2. ADA 40 mg EOW
                               Δ 28%                            3. IFX 3 mg/kg iv q8wks


                   12-month retrospective                 29%
                    observational study




                    p < 0.001                                                Etanercept n=319

                      Δ >7%                                                  Adalimumab n=313

                                8%                                           Infliximab n=107



         <1%
      Etanercept           Adalimumab                 Infliximab


                        1. Moots R et al. Ann Rheum Dis 2008;67(Suppl II):326 Abstract FRI0139 (EULAR 2008).
                        2. Wyeth data on file.
                                                               EULAR 2008 – SCIENTIFIC HIGHLIGHTS

Reasons for Dose Escalation in Anti-TNF
Therapy: DART Study

                                                                              Etanercept n=319
                     21%         12-month retrospective                       Adalimumab n=313
                                  observational study
                                                                              Infliximab n=107




                7%
                                       5%
                                                            3%
          <1%              0% <1%             0% <1%               <1% <1% <1%

            Inadequate     Loss of efficacy   Improved/ adequate      Other
                                                   response
             response

 Inadequate response is the primary cause for dose escalation in anti-TNFs.
                              1. Moots R et al. Ann Rheum Dis 2008;67(Suppl II):326 Abstract FRI0139 (EULAR 2008).
                              2. Wyeth data on file.
                                                                                           EULAR 2008 – SCIENTIFIC HIGHLIGHTS


Addition of Infliximab to FIN-RACo DMARD
Combination in Patients with early RA: NEO-RACo Study

•   DBRCT; N=100, RA<1y,
    No prior DMARD                                                                                *p=0.08; **p=0.40
                                                                             *
•   Initial FinRACo =
    (MTX+SSZ+HCQ+Pred)

•   IFX for 6m +FinRACO vs.    Percent of patients
    PBO + FinRACO in ERA
                                                                                                        **
    pts

•   IFX 3mg/kg at weeks 4,
    6, 10, 18 and 26.

•   Local glucocorticoid
    injections were allowed.




    Intensive use of FIN-RACo strategy in early active RA induced strict remission in 53% and sustained
         remission in 31% of patients. Adding infliximab during the first 6 months reflected in higher
      frequencies of remissions over time and prevented radiological progression during 2 years; it is
               however noteworthy that glucocorticoid injections were allowed in this study.

                                                     Leirisalo-Repo M, et al. Ann Rheum Dis 2008;67(Suppl II):50 Abstract OP-0009 (EULAR 2008)
                                                                                               EULAR 2008 – SCIENTIFIC HIGHLIGHTS


       Treatment of RA after Failure of TNF Antagonists:
       A Systematic Review and Meta-Analysis
•   Systematic literature review of
    publications and abstracts; 31                              Efficacy of 2nd and 3rd anti-TNF by Type of Failure
    studies from Jan 1995 – Nov
    2007, N=5306

•   Only 1 RCT; majority were
    prospective cohorts

•   Most of short duration      (60%
    <6months)
                                        Percent of patients



•   Primary reason for switch was due
    to efficacy failure (66%)

•   Assess efficacy of 2nd or 3rd TNF
    after failing a first anti-TNF




             Patients who switched due to primary failure with first anti-TNF agent, or who failed
                            two or more anti-TNF agents had poorer response.

                                                              Nalysnyk L, et al. Ann Rheum Dis 2008;67(Suppl II):326 Abstract FRI0125 (EULAR 2008)
CURRENT NON-ANTI-TNF BIOLOGICS
IN RA

• Abatacept
• Rituximab
                                                                      EULAR 2008 – SCIENTIFIC HIGHLIGHTS


  Assessment of Abatacept in Reducing Structural
  Damage Progression in RA: AIM Trial 3 Year Results
 • Patients entered open-label long-term extension of AIM after completing 1 year DBRCT
 • Abatacept given as approx. 10 mg/kg iv + MTX
 • Radiographs of hands & feet performed at baseline,1, 2 and 3 yrs, or early termination

At Baseline N=433                      Mean change (SD) Genant-modified Sharp score

                                  Baseline to Year 1             Year 1 to Year 2           Year 2 to Year 3
Radiographic assessment
                                    n=328 (76%)                   n=324 (75%)                n=295 (68%)

ES (Erosion)                            0.53 (1.45)                  0.25 (0.98)                0.14 (1.09)
JSN (Joint space
                                        0.35 (0.97)                  0.18 (0.64)                0.12 (0.70)
narrowing)
TS (Total score)                        0.89 (2.09)                  0.43 (1.41)                0.25 (1.61)
                      79% of non-progressors at yr 1, remained non-progressors in yr 2
                     73% of non-progressors during yr 2 remained non-progressors yr 3

         Abatacept provided increasing and significant degree of inhibition of structural damage
            progression in approximately two-thirds of patients who remained on treatment.

                                   Genant HK, et al. Ann Rheum Dis 2008;67(Suppl II):193 Abstract THU0179 (EULAR 2008).
                                                                                                                EULAR 2008 – SCIENTIFIC HIGHLIGHTS


Efficacy of Abatacept in RA patients with Inadequate
Response to Anti-TNF Therapy: Mean DAS28 Response
                                                  Overall, rates of LDAS & remission were 22.4% & 13.0%, respectively
                                                           Number of prior                            Prior                       Reason for
                                                             anti-TNFs                               anti-TNF                       failure
DAS28, change from baseline (mean) at 6 months




                                                   .0
                                                                                                                                   E*      I*     S*
                                                           1     2        ≥2    ≥3               ETN IFX ADA

                                                  -.5



                                                 -1.0



                                                 -1.5

                                                                                 -2
                                                 -2.0                                                           -2
                                                                           -2                      -2                              -2
                                                            -2       -2                                  -2
                                                                                                                                           -2
                                                                                                                                                  -2
                                                 -2.5                                 n=860                                 *E = Efficacy
                                                                                                                            *I = Intolerability
                                                                                                                            *S = Safety

                                                                                 Schiff M, et al. Ann Rheum Dis 2008;67(Suppl II):337 Abstract FRI0160 (EULAR 2008).
                                                                       EULAR 2008 – SCIENTIFIC HIGHLIGHTS


Efficacy of Abatacept in RA patients with Inadequate
Response to Anti-TNF Therapy: LDAS and Remission

•   Analysis from ARRIVE trial (6-month, open-label study) evaluating efficacy of abatacept (~10 mg/kg,
    based on weight range, given on days 1, 15, 29 and q4wk thereafter; efficacy assessed at 6 months) in
    1,046 patients with active RA, DAS28≥5.2, and inadequate response to ≥3 months anti-TNF-therapy.

                                 LDAS (low disease activity score)               Remission [% responders
     Patient subgroup
                                [% responders (95% CI)] at 6 months                (95% CI)] at 6 months
Number of prior anti-TNFs
1 (n=488)                                   24.8 (21.0, 28.6)                           15.8 (12.5, 19.0)
2 (n=340)                                   22.9 (18.5, 27.4)                            12.9 (9.4, 16.5)
≥ 2 (n=540)                                 20.0 (16.6, 23.4)                            10.6 (8.0, 13.1)
≥ 3 (n=200)                                 15.0 (10.1, 19.9)                             6.5 (3.1, 9.9)
Type of prior anti-TNF
ETN (n=278)                                 24.1 (19.1, 29.1)                           14.7 (10.6, 18.9)
IFX (n=348)                                 21.3 (17.0, 25.6)                           14.1 (10.4, 17.7)
ADA (n=351)                                 23.4 (18.9, 27.8)                            11.1 (7.8, 14.4)
Reason for failure
Efficacy (n=952)                            20.9 (18.3, 23.5)                           12.2 (10.1, 14.3)
Intolerability (n=230)                      22.6 (17.2, 28.0)                            13.5 (9.1, 17.9)
Safety (n=106)                              30.2 (21.4, 38.9)                            16.0 (9.1, 23.0)
            Efficacy of abatacept was generally comparable regardless of
             number or type of prior anti-TNF used or reason for failure.
                                       Schiff M, et al. Ann Rheum Dis 2008;67(Suppl II):337 Abstract FRI0160 (EULAR 2008).
                                                                               EULAR 2008 – SCIENTIFIC HIGHLIGHTS
      Efficacy of Abatacept in Delaying Development of RA in
      Patients with Undifferentiated Inflammatory Arthritis at High
      Risk of Developing RA

  •   DBRCT; N=56; 6 months treatment with abatacept (10 mg/kg by weight range) or placebo; no DMARDs allowed

  •   Patients had undifferentiated inflammatory arthritis (UA) and symptomatic clinical synovitis of ≥ 2 joints and anti-
      CCP2+ (patients with UA, positive for anti-CCCP2 antibodies are at high risk of progressing to RA)2

  •   Patients followed for 12 months for primary endpoint - proportion who developed RA by ACR criteria; 50/56
      patients were evaluable.
                                                  Time to discontinuation due to development of RA (lack of efficacy)

At 1 year, 46% of patients (12/26) treated
with abatacept developed RA vs 67%
(16/24) of placebo-treated patients.




   Abatacept may delay progression to
   definite RA in some patients with UA;
effects of abatacept were maintained for 6
       months after stopping therapy




                                           1. Emery P, et al. Ann Rheum Dis 2008;67(Suppl II):89 Abstract OP-0130 (EULAR 2008)
                                           2. Van Gaalen FA, et al. Arthritis Rheum 2004; 50(3):709-715
                                                                                         EULAR 2008 – SCIENTIFIC HIGHLIGHTS

Inhibition of Structural Damage in RA with
Rituximab at 2 Years: REFLEX Study
ITT analysis
       Total Sharp Score (TSS)




                                          * (p=0.0003)           ** (p=0.0019)                               *** (p<0.0001)




                                                                                                          ***
                                                         *
                                                                                 **




                                 Radiographs of hands and feet were obtained at BL, wk 24, wk 56 and wk 104.

                           Rituximab significantly inhibited structural damage progression over 2 years
                                   in RA patients with inadequate response to TNF Inhibitors.

                                                         Cohen S, et al. Ann Rheum Dis 2008;67(Suppl II):189 Abstract THU0167 (EULAR 2008).
                                                                           EULAR 2008 – SCIENTIFIC HIGHLIGHTS
  Which Subgroup of RA Patients Benefit from Switching to
  Rituximab vs. Alternative anti-TNF Agents After Failure to Anti-
  TNF Agent?

  • Prospective cohort nested within SCQM-RA cohort (Switzerland);
  • Patients failed at least one prior anti-TNF; further treatment with alternative anti-TNF or
    rituximab
  • N=300; 101 rituximab; 199 other anti-TNF:- ADA 56% (111/199); ETN 25% (50/199); IFX 19%
    (38/199)
  • 65% patients (195/300) with anti-TNF failure due to ineffectiveness (28% primary failure, 72%
    secondary failure); 35% patients (105/300) with anti-TNF failure due to an adverse event
                                         Outcome Measure at 6 months

                                                        Rituximab                    Alternative Anti-TNF Agent

   Prior failure in efficacy:
   DAS28 (95% CI)                                   -1.55 (-1.79, -1.31)                  -1.03 (-1.32, -0.75)

   Prior failure due to adverse event:
   DAS28 (95% CI)                                   -0.86 (-1.28, -0.44)                  -0.77 (-1.06, -0.48)


 Rituximab is more effective than switching to an alternative anti-TNF in patients who have persistent disease
despite use of anti-TNF. In instances when the motive for interrupting anti-TNF was other than ineffectiveness,
            both rituximab and alternative anti-TNFs appear to offer similar levels of effectiveness.

                                         Finckh A, et al. Ann Rheum Dis 2008;67(Suppl II):127 Abstract OP-0249 (EULAR 2008)
NEWLY EMERGING TREATMENTS IN RA
                                                            EULAR 2008 – SCIENTIFIC HIGHLIGHTS


 Certolizumab Pegol: Safety with MTX in Patients with
 Active RA: Pooled Results from RAPID 1 & RAPID 2

 • AE incidence rate presented as number of new cases per 100 patient-years


Treatment Emergent        PBO + MTX           CZP 200 mg + MTX                CZP 400 mg + MTX
Adverse Events (AEs)       (n=324)                 (n=640)                         (n=635)
Exposure (pt-yrs)           132.0                      406.7                           419.5
Related                      66.9                       78.1                            74.4
Serious AE                   11.9                       16.3                            16.6
AE leading to death          0.8                         0.7                             1.2
AEs leading to
                             3.8                         7.2                             7.0
withdrawal
Infections                   73.2                       80.9                            76.7
Serious Infections           1.5                         6.0                             7.1
Malignancies                 1.5                         2.0                             1.2
Cardiac disorders            5.3                         4.7                             4.8

                            Mease PJ, et al. Ann Rheum Dis 2008;67(Suppl II):324 Abstract FRI0120 (EULAR 2008).
                                                                                                       EULAR 2008 – SCIENTIFIC HIGHLIGHTS

   Radiographic Assessment at Week 16 in Certolizumab Pegol
   Treatment Failures (non-ACR20 at Week 12 and 14) from RAPID 1
   and RAPID 2: Post-hoc Analysis

                RAPID 1 PBO+MTX                               RAPID 1 CZP+MTX          RAPID 2 PBO+MTX              *
                                                                                                                 RAPID 2 CZP+MTX
                                                                                                                      *

                                               *Certolizumab (CZP) 200 mg + 400 mg treatment arms
                                              1.2
                     Mean Change at Week 16



                                                        1.0                             RAPID 1: n = 276/982 (28%) non-ACR20
                                              1.0                                       RAPID 2: n = 207/619 (33%) non-ACR20
                                                                    .8
                                               .8
                                                                                                                      †p≤0.05 by rank analysis
                                               .6                                  .5          .5
                                                                                                                 .4
                                               .4                                                                           †
                                                                                                                            .3
                                                    †           †                                                     †
                                                               .2        .2                                           .2
                                               .2                                  †     .1        †    .1
                                                                                                                                 .0
                                               .0
                                                               mTSS                           ES                          JSN
                                               Δ                               Δ                                  Δ
 In both trials, mean changes from baseline in mTSS, ES and JSN were significantly lower in the CZP+MTX arms
than in the PBO+MTX arms among patients withdrawing at week 16. The analysis supports previous observations
      that radiographic response not always associated with clinical response criteria and can occur earlier.

                                                         van der Heijde D, et al. Ann Rheum Dis 2008;67(Suppl II):51 Abstract OP-0011 (EULAR 2008).
                                                                                        EULAR 2008 – SCIENTIFIC HIGHLIGHTS


Golimumab: Efficacy in Patients with Active RA
Previously Treated with Anti-TNFs: Week 14 & 24 Results

                                     Primary Endpoint: ACR20 at Week 14                          ACR 20/50 at Week 24
                         50
                                                                                                       *
Percentage of Patients




                                                                                                     43.8


                         40                  37.9   *
                                         *
                                      35.3                                                       *
                                                                                              34.0


                         30
                                                                           20.3   *                                            *      *
                                                                                                                                   20.3
                         20   18.1                                  **
                                                                   16.3               16.8
                                                                                                                            18.3




                         10                                 6.5
                                                                                                                     5.2


                          0
                                     ACR20                        ACR50                      ACR20                         ACR50

                                                        PBO n=155         GLM 50 mg q 4 wk n=153        GLM 100 mg q4wks n=153
                                                                                                            * p<0.001; ** p<0.01 vs. PBO


                                                          Smolen J, et al. Ann Rheum Dis 2008;67(Suppl II):50 Abstract OP-0010 (EULAR 2008).
                                                                EULAR 2008 – SCIENTIFIC HIGHLIGHTS


Efficacy of Tocilizumab in RA Patients with Inadequate
Response to DMARDs: TOWARD Trial Week 24 Results

• DBRCT, N=1216, continued pre-study doses of DMARDs




                         *
Percent of patients




                                                                                  * p<0.0001

                                                *



                                                                       *




                         Gomez-Reino JJ, et al. Ann Rheum Dis 2008;67(Suppl II):194 Abstract THU0180 (EULAR 2008).
                                                                  EULAR 2008 – SCIENTIFIC HIGHLIGHTS


Efficacy of Tocilizumab in RA Patients with Inadequate
Response to anti-TNFs: RADIATE Trial Week 24 Results

• DBRCT, N=499, received PBO, TCZ 4 mg/kg iv or 8 mg/kg iv q4wks + MTX
• Primary Endpoint: ACR20 at 24 weeks




                               *

                                                                               * p<0.0001 vs. PBO
                                                                               **p=0.1005
  Percent of patients




                                                                               †p=0.0002
                         *                                    *


                                                      *
                                                                                             †

                                                                                    **




                               Emery P, et al. Ann Rheum Dis 2008;67(Suppl II):127 Abstract OP-0251 (EULAR 2008).
                                                                 EULAR 2008 – SCIENTIFIC HIGHLIGHTS


Efficacy of Tocilizumab Monotherapy vs MTX Monotherapy
in RA Patients: AMBITION Trial Week 24 Results

• DBRCT, N=570, received MTX 7.5 to 20 mg weekly, or TCZ 8 mg/kg iv q4wks
• Primary Endpoint: ACR20 at 24 weeks; primary analysis for non-inferiority used per protocol
  analysis, secondary analysis for superiority used intent-to-treat (ITT) analysis (n=570)



                               *
     Percent patients




                                                                                * p<0.0001
                                                                                **p=0.0023
                                                                                †p=0.0002
                                                            **

                                                                                         †




    TCZ monotherapy is clinically superior to MTX monotherapy. ALT elevations (>3X ULN)
     occurred more frequently with MTX (4%) vs. TCZ (2%). Shifts in total cholesterol from
              <200 mg/dl to ≥240 mg/dl occurred in TCZ 13% vs <1% with MTX.
                                    Jones G, et al. Ann Rheum Dis 2008;67(Suppl II):89 Abstract OP-0131 (EULAR 2008)
SPECIAL TOPICS
                                                                          EULAR 2008 – SCIENTIFIC HIGHLIGHTS

Anti-TNF Agents and Risk of Tuberculosis
(TB) Over 3 Years: RATIO Observatory
• Prospective cohort from 490 clinical departments in France by RATIO group

             67 cases of TB in 3 years; 60% women; median age 60.0 yr
          Last anti-TNF prior to TB: IFX (n=35); ADA (n=27); ETN (n=5)
                               (11   patients received more than 1 anti-TNF agent)
 Factors predictive of TB (multivariate analysis):

         Hazard Ratio (HR)
 Age:                                                                        1.04 (1.00 - 1.08); p = 0.03
 Origin from endemic areas:                                                  7.20 (1.66 – 31.19); p = 0.008
 Duration in months between first anti-TNF and TB:                           0.95 (0.92 – 0.98); p = 0.0006
 Using of Adalimumab vs. Etanercept:                                         10.05 (1.92 – 52.61); p = 0.006
 Using of Infliximab vs. Etanercept:                                         8.63 (1.38 – 53.78); p = 0.02

 Median total anti-TNF treatment duration before TB = 52 wk (range 6 - 321 wk)
 Incidence of TB:
 All anti-TNF therapy:                                                       39.2/100,000 patient years
 Infliximab OR Adalimumab:                                                   71.5/100,000 patient years
 Etanercept:                                                                 6.0/100,000 patient years
 General French population:                                                  8.7/100,000 patient years

 Increased risk of TB is higher with monoclonal antibodies than soluble receptor anti-TNFs.
                                             Tubach F et al. Ann Rheum Dis 2008;67(Suppl II):52 Abstract OP-0014 (EULAR 2008).
                                                                           EULAR 2008 – SCIENTIFIC HIGHLIGHTS

   Anti-TNF Agents and Risk of Tuberculosis
   (TB): BSR Biologics Register (BSRBR)
   • Prospective cohort involving 9882 anti-TNF treated RA patients vs. 2883 DMARD RA patients

Number of patients ever            DMARD        All anti-TNF         ETN                 IFX                ADA
received drug                     (n=2883)       (n=9882)          (n=5265)           (n=3569)            (n=3907)

Actively receiving drug, person
years (p-yrs)                      5196           22248            10187               6801                5260
Cases of TB                          0               20                4                 7                    9
Rate/100,000 p-yrs (95% CI)          -          90 (55, 139)      39 (11, 101)     103 (41, 212)        171 (78, 325)
IRR, adjusted for age, sex and
                                     -                -            Referent       2.81 (0.83, 9.46)   3.96 (1.24, 12.65)
year
Most recent drug exposure,
person years (p-yrs)               5196           26332             11970              8090                6272
Cases of TB                          0               29                6                 11                  12
Rate /100,000 p-yrs (95% CI)         -          110 (74, 158)    50 (18, 109)      136 (68, 243)        191 (99, 334)
IRR, adjusted for age, sex and
                                     -                -            Referent       2.84 (1.07, 7.53)   3.53 (1.34, 9,27)
year

                  Higher rates of TB were diagnosed in patients with IFX and ADA vs. ETN.
                   Vigilance for TB should be maintained after stopping anti-TNF therapy.

                                         Dixon WG et al. Ann Rheum Dis 2008;67(Suppl II):178 Abstract THU0134 (EULAR 2008).
                                                                                EULAR 2008 – SCIENTIFIC HIGHLIGHTS


Risk of Active TB Among Biologic-Naive RA Patients:
Retrospective Study in a US Claims Database

• Retrospective US cohort study using a health insurance database for 55 million people
  (Pharmetrics Patient-Centric Database)
     – Cases of incident TB: relevant diagnosis codes and 2 specific anti-TB antibiotics (one has to
       be isoniazid)

                                                                      Incidence rate
                           TB          Follow-up time                                                        RR*
                                                                       (/100,000 PY)
                          Cases             (PY)                                                           (95% CI)
                                                                          (95% CI)

RA cohort
                             4              100,414                 3.98 (1.09 – 10.2)               7.79 (2.40 – 25.3)
(N=55,996)†

Non-RA cohort
                             9             1,759,302                0.51 (0.23 – 0.97)
(N=945,258)†
PY, person years; CI, confidence interval; *RR = incident rate ratio of comparison of RA cohort with non-RA cohort.
†55,996 patients in RA cohort taking at least one DMARD, followed for 1.7 yr compared with 945,258 non-RA patients followed for

1.9 yr (matched for age, health plan, calendar time and duration of enrolment).


            In this large population of US patients, the risk of TB among RA patients was about 7-
             fold higher than among patients without RA, even in the absence of biologic therapy


                                                Mines D, et al. Ann Rheum Dis 2008;67(Suppl II):91 Abstract OP-0138 (EULAR 2008)
                                                                                                           EULAR 2008 – SCIENTIFIC HIGHLIGHTS


Risk of Elevated Liver Enzymes with TNF
Inhibitors in RA patients: CORRONA Database
• 6861 patients analyzed from Oct‟ 01– Mar‟ 07: 849 ADA, 1383 ETN, 1449 IFX
• Primary outcome was ALT and/or AST values >1x and >2x ULN


                                                3.0                      Adalimumab              Etanercept       Infliximab
                                                                                                                                   *
                                                                         *                             *
         Adjusted odds ratio for LFTs >2x ULN




                                                                     2.40          * p<0.05                           *         2.47
                                                2.5                                              2.38          2.32


                                                2.0                                1.81
                                                      1.72

                                                1.5
                                                              1.10                        1.06
                                                1.0
                                                                                                                          .68

                                                 .5

                                                 .0
                                                      Prevalent TNF-I Users         MTX + TNF-I only            New TNF-I Users
                                                             n=3461                    n=2414                     n=1455

     Overall incidence: >1X ULN =17.6%; >2x ULN= 2.1% (led to 5.6% discontinuation of therapy).
   Incidence of elevated LFTs most consistently observed with IFX, less with ADA, rarely with ETN.
                                                                        Furst DE, et al. Ann Rheum Dis 2008;67(Suppl II):52 Abstract OP-0015 (EULAR2008).
                                                                EULAR 2008 – SCIENTIFIC HIGHLIGHTS


Prophylaxis & Therapy of HBV Infection in Patients with
Rheumatic Diseases Treated with DMARDs or Biologic Agents

• N=22 consecutive patients with HBV infection on DMARDs or
  biologic agents as required by their underlying rheumatic disease
• Results:
  – 22 patients received lamivudine 100 mg given daily & well
    tolerated
  – Immunosuppressive therapy produced good results on the
    rheumatic diseases
  – Median follow-up was 15.5 months (range 1 – 47 months) after
    start of antiviral treatment
  – No cases of viral reactivation were observed

         Prophylaxis and therapy of HBV infection in patients with rheumatic diseases is
        feasible allowing for optimal immunosuppressive treatment in rheumatic patients.



                                   Zingarelli S. Ann Rheum Dis 2008;67(Suppl II):320 Abstract FRI0106 (EULAR 2008).
                                                               EULAR 2008 – SCIENTIFIC HIGHLIGHTS


Anti-TNF and Mortality: Results From The British
Society For Rheumatology Biologics Register (BSRBR)

• 11,738 patients in the BSRBR starting anti-TNF therapy for RA were
  prospectively followed until date of last physician follow-up or death,
  whichever was sooner. They were compared with a similarly recruited
  cohort of 2,959 subjects with active RA requiring DMARD therapy.
• Mortality rates were compared between the two groups
• Inverse probability of treatment weighting (IPTW) used to adjust for any
  confounding effect of differences in baseline variables.
• In total, there were 4,909 and 33,157 person-years of follow-up in the
  DMARD and anti-TNF cohorts respectively, during which time 87 DMARD
  and 551 anti-TNF patients died.
• RR of death in the anti-TNF treated cohort was 0.83 (95% CI 0.52 – 1.34)

 Compared to patients receiving standard DMARDs, anti-TNF therapy was not associated with
                         an increase in mortality in patients with RA.


                                    Lunt M, et al. Ann Rheum Dis 2008;67(Suppl II):66 Abstract OP-0053 (EULAR 2008)
                                                                                EULAR 2008 – SCIENTIFIC HIGHLIGHTS

Vaccination Response in Patients with RA
Undergoing Anti-CD20 Treatment
• Vaccination of patients with severe RA 6 months after treatment with anti-CD20 antibodies
  compared with RA patients treated with MTX (controls).
                                  Development of immune response†, ‡
                                                                                               Polysaccharide
                                               Protein vaccination*
                                                                                                vaccination**
      Anti-CD20 treated
                                                     9/10 patients†                             2/10 patients‡
       patients (N=10)
    MTX-treated patients
                                                    10/10 patients†                             6/10 patients‡
          (N=10)
*Influenza vaccine (Afluria); **Pneumococcal polysaccharides (Pneumo23); both vaccines administered to all patients; blood
samples collected 6 days post vaccination.
†B cells producing influenza specific antibodies present in 9/10 and 10/10 patients treated with anti-CD20 and MTX respectively;

Significantly lower number of cells producing influenza specific IgM in anti-CD20 treated patients vs MTX-treated patients
(p=0.02)
‡Polysaccharide specific response developed in 2/10 and 6/10 patients treated with anti-CD20 and MTX respectively (p=0.0003);

No difference detected in immunoglobulin secretion in response to Pneumococcal polysaccharides, between anti-CD20 treated
and MTX-treated patients.


RA patients treated with anti-CD20 develop adequate immune response to protein vaccination compared
                                    with polysaccharide vaccination.

                                          Bokarewa MI et al. Ann Rheum Dis 2008;67(Suppl II):189 Abstract THU0166 (EULAR 2008)
                                                                       EULAR 2008 – SCIENTIFIC HIGHLIGHTS

  Bone Mineral Density (BMD) in
  non-Menopausal Women with RA
  • Transversal study of non-menopausal women with RA (N=60); comparison of BMD (bone
    mineral density) measure dual energy X-ray absorptiometry (DEXA) at lumbar spine and
    hip compared to healthy non-menopausal women
      – Mean age 39.81±8.38 yr; median disease duration 7 yr; BMI 25.4±5.58 kg/m2;
        DAS28: 4.38±1.17; HAQ: 1.049±0.76.
      – 93.33% pts take average steroid dose of 5.87±2.91 mg; 83.3% pts take an average
        MTX dose of 10.26±3.54 mg/week.
  • Prevalence of osteoporosis - 10% at lumbar spine, 12.5% at hip.

                                           RA Patients                    Control
                                                                                                     P value
                                          (mean ± SEM)                 (mean ± SEM)
   Spine BMD (g/cm2)                       0.900 ± 0.13                  0.991 ± 0.11               <0.00001
   Hip BMD (g/cm2)                         0.825 ± 0.13                  0.915 ± 0.11                <0.0001
   BMD = bone mineral density

This preliminary study confirms BMD reduction in RA, independent of menopause; however, BMD reduction is
also linked to factors such as BMI, disease duration, HAQ and joint damage and cumulative corticosteroid use.


                                          Acheli D et al. Ann Rheum Dis 2008;67(Suppl II):79 Abstract OP-0097 (EULAR 2008)
ANKYLOSING SPONDYLITIS
                                                          EULAR 2008 – SCIENTIFIC HIGHLIGHTS
 Schematic Depiction of Sequence of Events in
 Ankylosing Spondylitis (AS) vs. Rheumatoid Arthritis
 (RA)
        Step 1               Step 2            Step 2b                          Step 3

                                                   INFLAMMATION                           OSTEO-
      INFLAMMATION           EROSIVE                                                   PROFILERATION
AS:     (fluctuating)         BONE               REPLACEMENT BY                        (SYNDESMOPHYTES)
                           DESTRUCTION            REPAIR TISSUE




      INFLAMMATION           EROSIVE
RA:     (persisting)          BONE
                           DESTRUCTION




                        Rheumatoid arthritis                                            AS structural
                            structural                                                  damage score
                          damage score                                                    (mSASS)


                                                                                     Time

                                                 From: Seiper J et al. Arthritis & Rheumatism 2008;58(3):649-656
                                                                         EULAR 2008 – SCIENTIFIC HIGHLIGHTS

Early Diagnosis of Ankylosing Spondylitis
by MRI
• Early Arthritis Clinic, Leeds,UK
   – N= 54 early ″pre-radiographic″ inflammatory back pain (IBP)
   – 62% male, mean age:30 yr, 54% HLA-B27+, 42 wk mean duration

                          Controls n=22 (11 with mechanical
                                                                                          IBP n=54
                               back pain + 11 healthy)
 Baseline                   27% (6/22) +MRI osteitis in SIJ*                 85% (46/54) +MRI osteitis in
 MRI                        and/or LS* (all in mechanical back pain)               SIJ* and/or LS*

 SIJ only                                        -                                     81.5% (n=44)
 LS only                                         -                                     23.5% (n=12)
 SIJ + LS                                        -                                     29.5% (n=13)
 Leeds Score >1                                0%                              42.6% mod-sev p<0.001
 *LS = lumbar spine; SIJ = sacroiliac joint

                     Spinal and SIJ involvement can occur simultaneously in early AS.


                            1. Marzo-Ortega H, et al. Ann Rheum Dis 2008;67(Suppl II):377 Abstract FRI0296 (EULAR 2008).
                                                                 EULAR 2008 – SCIENTIFIC HIGHLIGHTS

Early Diagnosis of Ankylosing Spondylitis
(AS) by MRI
• French AS Clinic, Tours, France2
  – 117 “pre-radiographic” suspected AS
  – MRI to detect AS lesions of Lumbar Spine (LS) &
    Sacroiliac Joint (SIJ)
• Results
  – 62.4% (73/117) +MRI for typical AS lesions
  – Lesions on LS & SIJ: 50.7% (37/73)
  – Lesions on LS only: 27.4% (20/73)
  – Lesions on SIJ only: 21.9% (16/73)
       Spinal and SIJ involvement can occur simultaneously in early AS; suspected AS
            patients with normal X-rays should consider MRI analysis if available.


                         1. Goupille P, et al. Ann Rheum Dis 2008;67(Suppl II):386 Abstract FRI0324 (EULAR 2008).
                                                                              EULAR 2008 – SCIENTIFIC HIGHLIGHTS

 Radiographic Progression in Ankylosing
 Spondylitis (AS)
 •   146 patients with AS (German Cohort)1,2

 •   81% male; symptom duration 23.6 ±11 yr; age 54.2 ±12 yr

 •   Syndesmophytes, ankylosis, spondylophytes retrospectively analysed (mSASSS) for detection of
     difference in radiographic progression over time1

 •   Fast progression defined as > 2 new syndesmophytes or >5 mSASSS units within 2 yrs2
                                                                        Anterior Vertebral         Posterior Vertebral
                                                                             Edges1                     Edges1
                                             Mean mSASSS1                              Syndesmophytes1
Baseline                                    20.5 ± 14.4 units                 27.1%                      12.6%
Follow-up (mean 3.8 ± 12 y)                 24.6 ± 15.9 units*                32%**                     15.7%**
Mean mSASSS Δ over 1 Year                    1.3 ± 2.5 units2               Overall Radiographic deterioration:1
                                           43% had 4X higher
                                                                                  153 Ant. Edges progressed
Progression of structural change          progression vs. mean
                                                                                  99 Post. Edges progressed
                                               mSASSS2
* p<0.001; ** p0.05


                   Radiographic progression is not linear over time in a large group of AS patients
                       and can occur fast; syndesmophytes show radiographic deterioration.

                                    1. Baraliakos X, et al. Ann Rheum Dis 2008;67(Suppl II):375 Abstract FRI0288 (EULAR 2008).
                                    2. Baraliakos X, et al. Ann Rheum Dis 2008;67(Suppl II):376 Abstract FRI0292 (EULAR 2008).
                                                                              EULAR 2008 – SCIENTIFIC HIGHLIGHTS


   Efficacy and Safety of Anti-TNF Agents for
   Ankylosing Spondylitis (AS)

                                                        IFX                          ETN                       ADA
                                           3 RCTs: n=264               IFX      5 RCTs: n=369             2 RCTs: n=246
                                                  vs. 127 PBO                  ETN vs. 266 PBO           ADA vs. 151 PBO
Odds Ratio (95% CI) for efficacy
(number of responders to therapy)
                                               8.70 (6.47, 11.70)             6.29 (5.20, 7.62)         4.43 (3.72, 5.27)

                                                  IFX vs. ADA                  ETN vs. ADA
Odds Ratio for relative efficacy                1.96 (1.39, 2.77)             1.42 (1.10, 1.84)                   -
                                                   (p=0.0001)                    (p=0.008)

                                                  IFX vs. ETN
Odds Ratio for relative efficacy                1.38 (0.97, 1.97)                       -                         -
                                                 (NS, p=0.072)
NNT (number needed to treat)                              3                             3                         4
Odds Ratio for safety (SAEs)                    2.25 (0.65, 7.79)             1.70 (0.72, 4.01)                N/A*
NNH (number needed to harm)                              52                            58                      N/A*
* Safety data for ADA were not included as it was based on only two studies with poor reporting




                                            Christensen R, et al. Ann Rheum Dis 2008;67(Suppl II): Abstract FRI0299 (EULAR 2008).
                                                                                EULAR 2008 – SCIENTIFIC HIGHLIGHTS

 Epidemiology of Hip Involvement in
 Ankylosing Spondylitis
 •   AS patients from ASPECT database (Belgium) N=847 and REGISPONSER database (Spain) N=1421

 •   ASPECT – hip involvement defined as previous or current hip arthritis; present in 27% patients

 •   REGISPONSER – hip involvement defined as pain or limitation of hips during clinical examination;
     present in 24% patients

                                                   ASPECT                                     REGISPONSER
Hip involved                         Yes (n=230)             No (n=617)              Yes (n=335)            No (n=1070)
Uveitis                                  36%*                     24%                   24%††                       20%
Enthesitis                               54%**                    48%                   35%†††                      29%
Anti-TNF started                        56%***                    39%                   25%***                      15%
Age at first symptoms                    23***                     28                    26†††                      27
BASDAI                                    5.6†                    5.2                    4.6***                     3.9
BASFI                                    5.8***                   4.8                    5.2***                     3.4
*p=0.001; **p=0.085; ***p<0.001; †p=0.009; ; ††p=0.114; ; †††p=0.041
BASDAI – Bath Ankylosing Spondylitis Disease Activity Index; BASFI – Bath Ankylosing Spondylitis Functional Index

Hip involvement is a common feature of AS involving about ¼ of patients; patients with hip involvement also
    had earlier disease onset. Patients with AS have higher disease activity, (higher BASDAI), & impaired
                                         functionality (higher BASFI).

                                     Vander Cruyssen B, et al. Ann Rheum Dis 2008;67(Suppl II):520 Abstract SAT0275 (EULAR 2008).
                                                                                   EULAR 2008 – SCIENTIFIC HIGHLIGHTS

   Risk Factors and Epidemiology of Hip
   Prosthesis in Ankylosing Spondylitis
   •    AS patients from ASPECT database (Belgium) N=847 and REGISPONSER database (Spain) N=1421

   •    ASPECT – hip prosthesis present in 6.2% patients with AS (39/628)

   •    REGISPONSER – hip prosthesis present in 3.8% of patients with AS (41/1092)

                                         ASPECT                           REGISPONSER                 Odds Ratio1 (95% CI)
Hip Prosthesis                Yes (N=39)         No (N=589)        Yes (N=41)         No (N=1051)
IBD                             17.9%*              8.7%             7.3%†††              4.8%           2.1 (1.04 – 4.4)
Uveitis                        28.2%**              27.7%             41.5%‡             21.5%
Enthesitis                     69.2%***              48%              48.8%‡             27.7%            2.3 (1.4 – 3.6)
Anti-TNF started                15.4%†              10.4%            26.8%‡‡             15.5%
AFS < 16 yr2                   33.3%††              14.8%            26.8%††              6.5%            5.5 (3.1 – 10)
AFS 16 to 21 yr2               33.3%***             22.2%            41.5%‡‡‡            27.5%             2.9 (1.7 – 5)
1Adjusted  odds ratio for multiple regression in overall group; 2Reference >21 years
*p=0.078; **p=0.094; ***p=0.01; †p=0.29; ††p<0.001; †††p=0.44; ‡p=0.003; ‡‡p=0.052; ‡‡‡p=0.002
IBD = inflammatory bowel disease; AFS = age at first symptoms



       Past or actual history of enthesitis, early onset of the disease and IBD are associated with most severe hip
                                              arthritis (i.e. hip prosthesis) in AS.

                                       Vander Cruyssen B, et al. Ann Rheum Dis 2008;67(Suppl II):384 Abstract FRI0318 (EULAR 2008)
                                                                                               EULAR 2008 – SCIENTIFIC HIGHLIGHTS

                      Golimumab in Ankylosing Spondylitis:
                      24-week Results of the GO-RAISE Study
                      •   DBPCT; N=356; patients received subcutaneous injections of golimumab 50 or 100 mg or placebo every 4 weeks.

                      •   Primary endpoint – proportion of patients with ≥ 20% improvement in the ASessment in AS working group (ASAS)
                          criteria at 14 weeks



                                                          *                                                      *p<0.001; †p<0.01
                                              *     *                                                            (change from baseline)
Percent of patients




                                                                                                *
                                                                                         *
                                                                                  *




                                                                                                                        *       †




                                                                 Braun J, et al. Ann Rheum Dis 2008;67(Suppl II):58 Abstract OP-0032 (EULAR 2008).
PSORIATIC ARTHRITIS & JUVENILE
IDIOPATHIC ARTHRITIS
                                                                                                   EULAR 2008 – SCIENTIFIC HIGHLIGHTS


         Etanercept-induced Remission in Juvenile Idiopathic
         Arthritis (JIA): German Etanercept Registry

         • Analysis calculated frequency of pre-defined „complete control‟ and „remission‟1
            N=909 ETN JIA patients; mean treatment duration 23 months (median 18 months)1
            • 50% patients (n=454) achieved „complete control‟
            • 32% (n=296) met „clinical remission on medication‟ criteria
            • 2.5% (n=22) had documented „drug free clinical remission‟
             Kaplan-Meier analysis showed 50% of patients reached complete control after 1 year
             Probability of remission was 50% after 2 years
             35% of patients reached drug free remission after 7 years

            „Complete control‟ or „Inactive disease‟ definition:2
             No joints with active arthritis
             No fever, rash, serositis, splenomegaly, or generalized lymphadenopathy due to JIA
             No active uveitis
             Normal ESR and/or CRP
             PGA score to indicate no disease activity


            „Remission‟ definitions:2
            1) Clinical Remission ON Medication: Criteria for Inactive Disease must be met for minimum of 6 continuous months while on medications
            2) Clinical Remission OFF Medication: Criteria for Inactive Disease must be met for minimum of 12 continuous months while off all anti-
            arthritis and anti-uveitis medications


                  Younger age at onset, less severe disease by CHAQ*, & less duration morning stiffness are
                positively correlated factors in complete control and remission for JIA patients treated with ETN.
                                                          1. Horneff G, et al. Ann Rheum Dis 2008;67(Suppl II):68 Abstract OP-0062 (EULAR 2008).
*CHAQ=Children‟s Health Assessment Questionnaire                                              2. Wallace CA et al. J Rheumatol 2004;31:2290-2294.
                                                                         EULAR 2008 – SCIENTIFIC HIGHLIGHTS


MMR Vaccination And Treatment of Juvenile Idiopathic
Arthritis With Methotrexate And Etanercept

•   One in three patients with juvenile idiopathic arthritis (JIA) are incompletely vaccinated due to uncertainty
    regarding efficacy in patients receiving MTX or TNF-antagonists

•   N=15 patients with JIA; N=22 healthy controls

•   Cell-based immunospot assay (ELLISPOT) detecting long-lived IFNγ (inteferon γ) producing T cells;
    virus-specific IgG antibodies investigated.




               MMR vaccination using attenuated live vaccines is effective in children with JIA
             treated with low dose methotrexate and/or etanercept simultaneous to vaccination.


                                          Borte S, et al. Ann Rheum Dis 2008;67(Suppl II):266 Abstract THU0412 (EULAR 2008)
                                                                              EULAR 2008 – SCIENTIFIC HIGHLIGHTS

 Sustained Improvement in Clinical Measures
 of PsA with Etanercept: 3 Year Outcomes
• 3-year data from an inception cohort in Belgian outpatient clinic; patients with
  PsA for at least 6 months and inadequate response to NSAID/DMARDs.
                                           Baseline              Year 1              Year 2               Year 3
   Patients receiving ETN                      37                  36                   32                  31
   Tender Joints                           10 (1 - 44)         1 (0 - 28)           0 (0 - 16)           0 (0-14)
   Swollen Joints                           9 (2 - 27)         0 (0 - 16)           0 (0 - 11)            0 (0-8)
   PASI (Psoriasis Area and
                                          1.75 (0 - 8.7)      0.7 (0 - 7.8)        0.8 (0 - 8.8)         0.6 (0-8)
   Severity Index)
                                               1.62              0.875                  0.5               0.875
   HAQ
                                           (0.5 - 2.63)        (0 – 2.13)           (0 – 2.25)           (0 – 2.5)
                                                26                 3.6                  2.3                 2.8
   CRP (mg/l)
                                           (0 - 215.4)         (0 - 96.3)           (0 - 58.1)          (0 - 186.8)
   % pts with dactylitis                     13.6%               2.7%                   0                    0
   Data expressed as medians and ranges

     8 (21.6%), 10 (27.7%) and 15 (48%) of patients in clinical remission at 1, 2 and 3 years, respectively.

Etanercept resulted in sustained improvement in arthritis, dactylitis, psoriasis, inflammation and quality of
life associated with active PsA over 3 year of treatment; clinical remission with etanercept as a sustainable
                                          goal is possible in PsA.

                                            de Vlam K, et al. Ann Rheum Dis 2008;67(Suppl II):525 Abstract SAT0290 (EULAR 2008)
                                                               EULAR 2008 – SCIENTIFIC HIGHLIGHTS


Golimumab, A New TNF-alpha Antibody: Psoriatic
Arthritis Efficacy Results: GO-REVEAL Study
                      Week 24                                Week 52 (open-label)
      LOCF analysis       PBO: n=113      GLM                                 GLM 50 mg: n=102
                          50 mg: n=146 GLM 100                                GLM 100 mg: n=135
                          mg: n=146
      All comparisons GLM 50 mg vs. PBO and
      GLM 100 mg vs. PBO significant at p<0.001.




                           Kavanaugh A, et al. Ann Rheum Dis 2008;67(Suppl II):99 Abstract OP-0161 (EULAR 2008).
                                                                EULAR 2008 – SCIENTIFIC HIGHLIGHTS


Golimumab: Efficacy in Nail PsO, Enthesitis, and
Dactylitis in PsA Patients: GO-REVEAL Study

                           Week 24 Results                               *

       PBO: n=113                                                                        *p<0.001
       GLM 50 mg: n=146
       GLM 100 mg: n=146
                                                                                                 *
                                                *
                                         *                                                 *
                     *


               *




                                             (not median % Δ)




                           Gladman D, et al. Ann Rheum Dis 2008;67(Suppl II):526 Abstract SAT0292 (EULAR 2008).
                                                                                           EULAR 2008 – SCIENTIFIC HIGHLIGHTS


                      Golimumab in Psoriatic Arthritis:
                      Response to Pneumococcal Vaccine (GO-REVEAL Study)

                      •   DBRCT; N=292 golimumab-treated, N=113 placebo-treated; patients received subcutaneous injections of
                          golimumab 50 (N=146) or 100 mg (N=146) or placebo every 4wk

                      •   Pnemococcal vaccine (Pneumovax 23 (North America) or Pneumovax 11 (Europe) administered at wk 12
                          to 87% of patients in each treatment group (249 golimumab-treated, 92 placebo-treated)
Percent of patients




                                There was no correlation between treatment group (p=0.072) and vaccine response, but
                                absence of baseline MTX use (p=0.0036) significantly correlated with vaccine response


                                                           McInnes I, et al. Ann Rheum Dis 2008;67(Suppl II):529 Abstract SAT0302 (EULAR 2008)
                                                                                  EULAR 2008 – SCIENTIFIC HIGHLIGHTS


        Phase 2 study of Ustekinumab (Human Interleukin-12/23)
        in Psoriatic Arthritis: Study Design
     Group 1          Ustekinumab Wks 0, 1, 2, 3. Placebo Wks 12 and 16.
      (N=76)


                R




     Group 2          Placebo Wks 0, 1, 2, 3. Ustekinumab Wks 12 and 16.
      (N=70)
       Week         01234               8         12           16          20          24         28                      36
                                               Primary
                                                                                                                    Final Safety
                                               Endpoint
                                                                                                                     & Efficacy
      = Ustekinumab injection                   ACR20
                                                                                                                    Evaluation
     Changes to the study drug preparation during the trial resulted in a change of the ustekinumab dosing;
     •17 subjects received at least 1 dose of 90 mg at either Weeks 0,1,2, and/or 3
*
     •59 subjects received 63 mg weekly x 4.
     •70 subjects were randomized to placebo; 56 of 70 subjects received 63 mg x 2 beginning Week 12

    Patients recruited from Dermatology practices; Rheumatologists supervised joint assessments
    20% with prior anti-TNF exposure
                                                 Gottlieb AB, et al. Ann Rheum Dis 2008;67(Suppl II):99 Abstract OP-0162 (EULAR 2008)
                                                                          EULAR 2008 – SCIENTIFIC HIGHLIGHTS

           Phase 2 study of Ustekinumab (Human
           Interleukin-12/23) in Psoriatic Arthritis
         • RPCT; patients received either ustekinumab (USK) 90 mg/63 mg (N=76) at weeks 0, 1, 2
           and 3, followed by placebo at weeks 12 and 16, or placebo at weeks 0, 1, 2 and 3, followed
           by USK 63 mg at weeks 12 and 16 (N=70)
Percent of patients




                            *
                                                                             *p<0.001; **p=0.004; †p=0.005, all vs PBO


                                                          **


                                                                                                †




                                         Gottlieb AB, et al. Ann Rheum Dis 2008;67(Suppl II):99 Abstract OP-0162 (EULAR 2008)

				
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