2. Agenda Spondyloarthropathies Early Rheumatoid Arthritis Established Rheumatoid Arthritis Benefit - Risk Dr. Jad OKAIS HDF 2009

3. Agenda Spondyloarthropathies Early Rheumatoid Arthritis Established Rheumatoid Arthritis Benefit - Risk

4. Spondyloarthropathies Early treatment By Anti-TNF InflammationAnkylosis Year 1 Year 10 Year 20 Late treatment By Anti-TNF

6. Arthritis & Enthesopathies

7. Anti-TNF treatment in AS In general, about half of the patients gain 50% improvement of disease activity as assessed by the Bath Ankylosing Spondylitis Activity Index (BASDAI). 30–40% show an increase in function as assessed by the Bath Ankylosing Spondylitis Functional Index (BASFI). Applying the ASAS outcome criteria usually >60% reach ASAS 20, and >40% the ASAS 40 and ASAS 5/6 criteria, while 20–30% even achieve ASAS partial remission. Furthermore, AS patients treated with TNF blockers report an improved quality of life and reach higher productivity scores. There is very good efficacy on clinical disease activity, acute-phase reactants an inflammation visible on MRI. 1- Braun J,et al. Improvement in patientreported outcomes for patients with ankylosing spondylitis treated with etanercept 50mg once-weekly and 25mg twice-weekly. Rheumatology 2007;46:999–1004. 2- Davis JC et al. Health-related quality of life outcomes in patients with active ankylosing spondylitis treated with adalimumab: results from a randomized controlled study. Arthritis Rheum 2007;57:1050–7. 3- Van der Heide et al. Infliximab improves productivity and reduces workday loss in patients with ankylosing spondylitis: results from a randomized, placebo-controlled trial. Arthritis Rheum 2006;55:569–74. 4- Rudwaleit M et al. Prediction of a major clinical response (BASDAI 50) to tumour necrosis factor alpha blockers in ankylosing spondylitis. Ann Rheum Dis 2004;63:665–70.

8. Better response to TNF blockers with early treatment 10 30 50 70 90 < 10 years N=37 11-20 years N=33 >20 years N=29 Patients with AS treated with INFLIXIMAB Patients achieving BASDAI 50 Rudwaleit M, et al. Ann Rheum. Dis. 2004;63:665-70

9. Anti-TNF and Syndesmophytes Growing syndesmophytes and ankylosis seems not to be inhibited by anti- TNF therapy some unresolved methodological issues : –historical cohorts are only included –the inability to assess the thoracic spine by standard radiography –the low sensitivity of the currently used modified Stokes AS spinal score scoring –the degree of damage: one (mean) new syndesmophyte developing in the whole spine over two years. –continuous NSAID therapy may reduce radiographic progression in AS ( placebo group) Baraliakos X, Listing J, Rudwaleit M et al. Progression of radiographic damage in patients with ankylosing spondylitis: defining the central role of syndesmophytes.Ann Rheum Dis 2007;66:910–5. Baraliakos X, Listing J, Brandt J et al. Radiographic progression in patients with ankylosing spondylitis after 4 yrs of treatment with the anti-TNF-alpha antibody infliximab. Rheumatology 2007;46:1450–3. van der Heijde D, Landewe´ R, Braun J et al. Radiographic progression of ankylosing spondylitis after up to two years of treatment with infliximab. Arthritis Rheum 2008. Wanders A, van der Heijde D, Landewe´ R, et al. Nonsteroidal antiinflammatory drugs reduce radiographic progression in patients with ankylosing spondylitis.Arthritis Rheum 2005; 52:1756– 1765.

10. Link between the presence of inflammation at the vertebral corner on the MRI and sydesmophytes on plain rx The presence of inflammation is associated with the development of new syndesmophytes The presence of inflammation is associated with the development of new syndesmophytes even when inflammation is suppressed with anti-TNF treatment A new syndesmophyte can occur even when initial RX and MRI are normal Walter P. et al. inflammatory lesions of the spine on MRI predict the development of new syndesmophytes in SA. A&R, 60;1; 2009 pp 93-102

11. Infliximab lessens cellular infiltration in bone marrow

12. RA SA

13. Wnt proteins and Dickkopf-1 (DKK-1) Diarra D et al. Dickkopf-1 is a master regulator of joint remodeling. Nat Med 2007;13:156–63.

14. DKK (Dickkopf) Level in RA and AS Diarra D, et al. Nature Medicine 2007;13(2):156 0 5 10 15 20 25 30 35 0 week anti-TNF 2 week anti-TNF 6 week anti-TNF HealthyRAAS DKK-1 Serum level (pg/ml) * ** *

15. Conclusion : TNF blockers indeed do not inhibit syndesmophyte formation in AS. Data with longer follow-up, with the antibodies against TNF in patients with early disease, will give us the final answer concerning the inhibition of syndesmophyte formation.

16. Ankylosing Spondylitis Early Pre-radiographic Axial SpA

17. The Inflixispine Study Barkham et al. Arthritis Rheum. 2009; 60(4):946-954 Objective: To evaluate the efficacy of IFX in HLA-B27 + pts with MRI-determined early sacroiliitis Patients: HLA B27+, Inflammatory Back Pain (Calin criteria) and MRI determined sacroiliitis  40 pts included, mean age: 28.8 years, 75% male, mean symptom duration: 15.3 months. Protocol: Infliximab 5 mg/kg (n=20) or placebo (n=19/20) infusions at 0, 2, 6 and 12 weeks  FU every 4 wks from wk 16 to wk 40 or time to active disease (BASDAI>4) Pts with active disease  open label IFX infusions after wk 16

18. Baseline characteristics InflixiSpine (n=40) Age, mean years28.8 ( ±7.6) % female25 HLA-B27 positive100 Disease duration, years mean (range)* or median (±SD) 1.3 (±0.73) % MRI positive100 % Both HLA-B27 and MRI positive 100 % with IBP100 BASDAI, mean (range)5.86 (±0.73) Haibel et al. Arthritis Rheum. 2008; 58(7):1981-1991; Barkham et al. ACR 2007. Abstract L11.

19. . HLA-B27 + Very Early Pre-radiographic AS - Treatment with IFX* Primary endpoint: change in MRI scores from baseline to week 16 62.7% 29.4% P=0.001 0 50 100 % of lesions resolving 47/75 20/68 Sacroiliac MRI lesions resolved New sacroiliac MRI lesions 1.2% 12% 0 5050 100 % new lesions P=0.004 PBO (n=20) IFX (n=20) Patients with spinal lesions resolved 0 50 100 % of patients 60% 25% 3/5 1/4 n=9 (pts with spinal lesions at BL) P=0.016 Barkham et al. EULAR 08 FRI0310 Barkham et al. Ghent SpA 08 poster All 3 criteria – IBP – HLA-B27 – MRI inflammation of spine or SI joints * IFX 5mg/kg w0, w2, w6, w12

20. Barkham et al. Arthritis Rheum. 2009; 60(4):946-954 Clinical Efficacy of IFX in HLA-B27 + Very Early AS: Secondary Endpoints p = 0,009 p = 0,053 p = 0,009 Week 16

21. Infliximab Therapy in Patients with HLA B27 Positive Very Early Ankylosing Spondylitis ** **p=0.009 Pts treated with PBO or IFX 5 mg/kg at 0, 2, 6 and 12 weeks (RCT), FU from week 16-40. If pts developed active disease (BASDAI>4), they received OL IFX after week 16 *p=0.002 * Week 16 Barkham et al. EULAR 09 OP-0016 Week 16

22. Remicade Therapy in Patients with HLA B27 Positive Very Early Ankylosing Spondylitis ** **p=0.009 Pts treated with PBO or IFX 5 mg/kg at 0, 2, 6 and 12 weeks (RCT), FU from week 16-40. If pts developed active disease (BASDAI>4), they received OL IFX after week 16 *p=0.002 * Week 16 Barkham et al. EULAR 09 OP-0016 Remission induction approach works in early AS, (8/20) 40% of the patients are biologic-free Week 16 PBO IFX Short course of IFX  continued suppression of disease activity in early AS pts with sustained benefit in QoL, function and disease activity. 40% of the pts remained in a low disease activity state for 28 weeks off IFX after 4 IFX infusions. * *p=0.035 vs PBO Number of pts requiring OL IFX

23. Barkham et al. Arthritis Rheum. 2009; 60(4):946-954 Clinical Efficacy of IFX in HLA-B27 + Very Early AS: Conclusions Remicade appears to be an effective therapy for very early inflammatory back pain. This is the first therapy to show suppression of the inflammatory lesions on MRI in very early Ankylosing Spondylitis. Compared to studies of TNF blockers in established disease, the proportion of patients achieving ASAS partial remission was much higher suggesting a clear benefit for early treatment.

24. *p=0.047; **p=0.006 vs. AAS group 24 Gu et al. EULAR 09 OP-0017 Efficacy and Predictive Parameters for Treatment of Early AS Using Remicade The efficacy for Remicade in EAS patients is significantly better than that in AAS. In addition, the clinical improvements by ASAS20, ASAS50 and ASAS70 at week 2 for EAS patients (one infusion of IFX) is a strong predictor of subsequent clinical responses to IFX treatment at week 12. Percent of Patients * Week 12 ** Open-label non-randomized study, 3 infusions IFX 5 mg/kg at week 0, 2, and 6. Group 1 early active AS (EAS) (n=60) -dis. Course > 6 months, < 2 yrs -ESSG criteria but not NY criteria - BASDAI > 4 -Score SJ MRI > 4 (ASspiMRI acute score Group 2 active AS (AAS) (n=40) -NY criteria - BASDAI > 4

25. Ankylosing Spondylitis Long-Term Efficacy

26. EASIC – European Ankylosing Spondylitis Infliximab Cohort Three abstracts submitted to EULAR 09: EASIC 5 years: –Outcomes (European Ankylosing Spondylitis Infliximab Cohort (EASIC): Outcome of patients who had discontinued infliximab after the end of ASSERT) –Long-Term efficacy (European Ankylosing Spondylitis Infliximab Cohort (EASIC): Long-Term (5 years) Efficacy of Remicade on disease activity and function – A real life experience after the end of ASSERT –Safety (European Ankylosing Spondylitis Infliximab Cohort (EASIC): Safety of long term therapy with Remicade in patients with ankylosing spondylitis (AS)

27. EASIC – European Ankylosing Spondylitis Infliximab Cohort Background: insufficient knowledge of long term safety and efficacy of anti- TNF therapy in AS EASIC-study: Open label extension of ASSERT Brandt et al. EULAR 08 FRI0305, ClinicalTrials.gov identifier: NCT00237419

28. A Randomized, Double-blind Trial of the Efficacy of REMICADE ® (Infliximab) Compared with Placebo in Subjects with Ankylosing Spondylitis Receiving Standard Anti- inflammatory Drug Therapy

29. ASSERT Study Design Screening Patients (N=357) RANDOMIZATIONRANDOMIZATION Placebo (N=78) Infliximab 5 mg/kg (N=201) Wk 0Wk 2Wk 6Wk 12Wk 18Wk 24 Endpoint Assigned to treatment (N=279) Failed Screening (N=78) Van der Heijde et al., Arthritis & Rheumatism 2005, 52: 582 3/8 ratio

30. EASIC – European Ankylosing Spondylitis Infliximab Cohort Background: insufficient knowledge of long term safety and efficacy of anti- TNF therapy in AS EASIC-study: Open label extension of ASSERT Time course: ASSERT N=279 2 years Mean: 1,3 + 0.9 yrs 96 weeks EASIC N=103 15% did not receive IFX continuously between ASSERT and EASIC Brandt et al. EULAR 08 FRI0305, ClinicalTrials.gov identifier: NCT00237419 5 years total

31. EASIC – European Ankylosing Spondylitis Infliximab Cohort ClinicalTrials.gov identifier: NCT00237419 Completers at 96 weeks n=4 n=5 n=76

32. EASIC – European Ankylosing Spondylitis Infliximab Cohort: Outcomes at 96 weeks in Group 1 Group 1A: discontinuation and relapse (n=9)  44% (4/9) patients still on IFX  Mean BASDAI 6.7 + 2.4 start of EASIC  3.5 + 2.4  Reasons for dropping: 3/5 = infusions reactions 97 + 22 days after screening 1/5 = lack of efficacy 1/5 = lost to FU Group 1B: discontinuation and remission (n=5)  1/5 remains on remission at week 96  4/5 relapses after 61+ 50 days  1 switched to ADA  3/4 treated with IFX Overall 5 patients in Group 1 completed the study under therapy with IFX, mean BASDAI = 1.8 + 1.3 after 96 weeks. One pt remained in drug-free remission. 2/3 dropped out after 89 + 29 days of Tx (1 IR and 1 lack of efficacy) Heldmann et al. EULAR 09 SAT0259

33. EASIC – European Ankylosing Spondylitis Infliximab Cohort: Long- Term efficacy in Group 2 Completers Group 2 (n=76/88) At the end of EASIC: 78% pts had no arthritis and 85% no enthesitis Heldmann et al. EULAR 09 SAT0258

34. EASIC – European Ankylosing Spondylitis Infliximab Cohort: Safety Remicade is well tolerated and safe for AS patients over ~ 5 years. Infections were the most common adverse events. Less than 10% developed infusion reactions. TotalGroup 1 (n=15) Group 2 (n=88) Ratio Gp2/Gp1 5.8 Number of AEs 545 70 4756.8 Patients with AEs 88 (85.4%) 13755.8 Infections257272308.5 Serious Infections303- Tuberculosis000- Malignancies000- Uveitis8351.6 Infusion reactions201640.25 Heldmann et al. EULAR 09 SAT0259

35. Long-term efficacy of aTNFs in patients with active Spondyloarthritis ETN 1 IFX 2 IFX 3 ADA 4 ETN 1 IFX 2 3 yrs4 yrs6 yrs8 yrs Adherence (%) 81.062.377.867.365.453.6 BASDAI 50 (%) 63.067.558.067.6 ASAS 20 (%) 81.881 PR (%)35.039.435.535.1 1 Baraliakos et al. EULAR 09 AB0428, 2 Baraliakos et al. EULAR 09 SAT0284, 3 Devinck et al. EULAR 09 SAT0278, 4 van der Heijde et al. EULAR 09 SAT0254. Similar therapy adherence and efficacy data for the TNF blockers

36. Devinck et al. EULAR 09 SAT0278 Long-term efficacy/safety of IFX in patients with active Spondyloarthritis: Results of an 8-Year FU SpA with active axial and/or peripheral disease were treated with 5 mg/kg IFX q8 (AS: 63 pts; PsA: 36 pts; und. SpA: 10 pts). Dec. 2008: 617 patient-yrs reached. A highly significant improvement in all disease manifestations was maintained over a FU period up to 8 years. No new safety signals. BaselineYr 1Yr 2Yr 3Yr 4Yr 5Yr 6Yr 7Yr 8 Nr pts10710190 7761493211 Pt global6620171220 3020 Pt pain6122161120 25 ESR2010 897795 CRP2,000,600,400,300,250,200,300,20 Nr AS pts63595349413023116 BASDAI5121169101312228 BASFI583927 2327213920 Belgian Cohort 47 patients had peripheral arthritis at baseline (25 oligo-, 22 polyarticular), mostly were PsA and IBD related SpA All patients reached the 6 yrs evaluation

37. 0 1 2 3 4 5 6 7 012245478102132156182206230254 weeks mean value BASDAI BASFI BASMI Long-Term Sustained Clinical Response of Infliximab Therapy in AS Braun et al. Ann Rheum Dis. 2008;67(3):340-345 Completer analysis IFX proved to be safe and efficacious over 8 years Baraliakos et al. EULAR 09 SAT0284

38. % pts treated in partial remission Patients in Partial Remission after 5 years of Treatment with Remicade 0 10 20 30 40 50 60 70 012245478102132156182206230254 weeks Completer analysis Braun et al. Ann Rheum Dis. 2008;67(3):340-345 35.1 % of patients in partial remission at 8 years! Baraliakos et al. EULAR 09 SAT0284

39. Persistent clinical efficacy/safety of Remicade in patients with AS over 8 years 69 pts with active AS were included in RCT. 43 pts completed year 3 (FU1). 53.6% (37/69) finished Year 8 (FU2). Pts were treated with 5mg/kg IFX i.v. q6 “BRAUN” Study Baseline n= 69 FU 1 (Year 3) n= 43 FU 2 (Year 8) n= 37 BASDAI mean 6.42.52.3 BASDAI 50% % (n) 63% (27/43)67.6% (25/37) ASAS 20% % (n) 81% (30/37) ASAS 40% % (n) 62% (23/37) PR % (n)35.1% (13/37) Remicade is safe and efficacious in patients with AS over 8 years period. Majority of patiens remained on treatment with low disease activity. 21 patients (57%) showed sustained ASAS20% response between Week 24 and FU2

40. Psoriatic Arthritis Efficacy of Treatment in Early Polyarticular PsA

41. REmicade Study in Psoriatic arthritis patients Of methotrexate-Naïve Disease: The RESPOND Study PsA pts, naïve to MTX and anti-TNFs n=115 IFX 5 mg/kg; wk 0, 2, 6, 14 + MTX 15 mg/week n=57 0 Week MTX 15 mg/week n=58 261416 Study visits PE: ACR 20 at wk 16 Study design: Randomized, prospective, open-label, multi-center, multi-national study Inclusion criteria: Patients >18 years of age Diagnosis of Psoriatic Arthritis with peripheral polyarticular involvement Disease duration  3 months prior to screening. Active PsA = ≥5 swollen and tender joints, + one of the following: ESR≥28 mm/hr, CRP≥15 mg/L or morning stiffness≥45 min Pts naïve to MTX, anti-TNF agents, and could not be on DMARDS Nasonov et al. EULAR 09 OP0196

42. Baseline Characteristics IFX + MTXMTX alone Gender (Males) 4861.1 Mean Age  SD 40.1  12.342.3  10.5 Mean Disease Duration 2.8 yrs3.7 yrs Tender joint count, mean (SD) 21.1 (13.32)20.1 (11.24) Swollen joint count, mean (SD) 15.1 (10.07)14.3 (9.47) CRP, mean (SD) 29.0 (38.83)25.3 (26.11) DAS28, mean (SD) 5.16 (1.074)5.07 (1.178) PASI, mean (SD) 8.27 (10.197)11.62 (12.535) Nasonov et al. EULAR 09 OP0196 RESPOND

43. IFX Plus MTX Significantly Improves Synovitis and Psoriatic Lesions in MTX-naïve PsA Patients Outcomes at week 16: PE (ACR 20) is met and significant improvement in other endpoints, IFX + MTX vs. MTX alone Early MTX-naïve PsA patients with active disease achieved significantly greater ACR response rated and improvement in PASI scores when treated with IFX+MTX compared to MTX alone % of patients p<0.05 p<0.01 p<0.0001 Nasonov et al. EULAR 09 OP0196 RESPOND Randomized, prospective, open-label, 16 week (ITT analysis) IFX + MTX MTX

44. MTX-naïve PsA Patients Respond Rapidly to IFX+MTX Therapy Outcomes at week 6: IFX + MTX treated pts attain a response significantly more rapid then MTX alone treated pts A significantly greater proportion of MTX naïve PsA patients – when treated with IFX+MTX – attain an early response to treatment in terms of arthritic and psoriatic signs and symptoms compared to MTX alone Nasonov et al. EULAR 09 SAT0353 RESPOND Randomized, prospective, open-label, 16 week (ITT analysis) IFX + MTX MTX p<0.0001 p=0.0042 p=0.003 p<0.0001 PASI 75* *Pts with BL PASI  2.5 6 weeks

45. Psoriatic Arthritis Efficacy

46. Mak et al. EULAR 09 SAT0345 The Best for Pso and PsA - UST (90 mg shows superior efficacy compared to all biologics except Remicade The Best Biologic for Pso and PsA - UST ( ustekinumab) 90 mg shows superior efficacy compared to all biologics except Remicade Meta-analysis of 25 RCTs (n=9889 pts, mean age 44.1 yrs) No superiority OR for PASI 75 vs UST 90 mg at wks 0 and 4 For PsARC Remicade better than ADA (OR 1.51) with no stat. difference between ADA, ETN, EFA, ALE PsO: UST 90mg is superior to all biologics except Remicade PsA: Remicade is the best biologic Toxicity and safety profiles of all biologics are comparable

47. Summary Ankylosing Spondylitis Short course IFX – Biologic-free remission induction in early axial AS EASIC – long-term data 8 years long-term data: q8 (Belgian cohort) 8 years long-term data: q6 (Braun) Psoriatic Arthritis 2 abstracts on RESPOND - MTX-naïve PsA Best biologic of choice

48. Agenda Spondyloarthropathies Early Rheumatoid Arthritis Established Rheumatoid Arthritis Benefit - Risk

49. 1.Sequential monotherapy 2. Step-up combination therapy Initial MTX Initial Combo 3. Initial combination with high prednisone 4. Initial combination with infliximab BeSt Comparison of Four Treatment Strategies

50. Group 4 Group 3 Group 2 Group 1 Treatment Strategies in the BeSt Study MTX + Infliximab SSZ LEF MTX + CSA + PRED MTX + SSZ + PRED MTX + CSA + PRED MTX + Infliximab MTX MTX + SSZ MTX + SSZ + HCQ MTX + SSZ + HCQ + PRED MTX + Infliximab MTX SSZ LEF MTX + Infliximab Goekoop-Ruiterman et al, 2005 Arthritis Rheum 52: 3381-90

51. 2 to 3-monthly treatment adjustments based on DAS 44 - scores:  DAS 44 >2.4  next step  DAS 44 < 2.4  continue therapy Taper/Discontinuation  Restart:  DAS 44 < 2.4 for ≥6 months medication  Taper to maintenance dose  DAS was ≤1.6 for ≥6 months after 2 yrs  Discontinuation last DMARD  DAS increased to ≥1.6  Restart with last DMARD Treatment Strategies in the BeSt Study Goekoop-Ruiterman YPM et al., Arthritis Rheum 2005;52(11):3381-3390

52. 0% 20% 40% 60% 80% 100% Group 1Group 2Group 3Group 4 % of patients DAS<1.6** Klarenbeek et al. EULAR 08 THU0162 BeSt 5 Year Results: Remission** ** Includes ALL patients in remission (on drugs and off IFX and DMARDs) “With DAS-steered, tight- controlled treatment, 48% of all patients achieved biologic free remission” Achieved with initial treatment step 81% 39% 46% 65% * *p<0.001 Gr 4 vs Gr 1&2

53. Median Change in vdH-S Score after 4 years of FU Overall p = 0.007 BeSt: Prevention of Rx Progression Median change 4.8 5.5 3.0 2.8 van der Kooij SM et al., ACR 2007, abstract 697

54. Sustained benefit of initial combination therapy in the amount of joint damage after 5 years Median Change in vdH-S Score after 5 years of FU 1 and 2 vs 4 p<0.01 Median change 3.5 2.5 1.0 1.0 Even a short period of early better suppression of disease activity still defines the amount of joint damage 5 yrs later Klarenbeek N. et al. EULAR 09 SAT0013

55. Sustained benefit of initial combination therapy in the amount of joint damage after 5 years Median Change in vdH-S Score after 5 years of FU 1 and 2 vs 4 p<0.01 Median change 3.5 2.5 1.0 1.0 Klarenbeek N. et al. EULAR 09 SAT0013 Annual SHS progression rates: highest in year 1 with significantly more progression in group 1 and 2 than in group 3 and 4 In yrs 2-5, joint damage progression between the four arms was comparable

56. Agenda Spondyloarthropathies Early Rheumatoid Arthritis Established Rheumatoid Arthritis Benefit - Risk

57. Remission induction with Remicade: First report on biologic-free remission in established RA 100 RA pts with DAS28<3.2 for 6 months discontinued Remicade ~40% pts could stop IFX therapy for > 1 year without progression of structural damage Y. Tanaka et al. EULAR 09 OP-0150

58. 7 Year FU of IFX in RA pts refractory to multiple DMARDs treatment: attrition and long-term effect Vander Cruyssen et al. Arthritis Res Ther. 2006;8(4):R112; Vander Cruyssen et al. EULAR 09 THU0181 511 RA pts with 10 yrs disease duration; IFX 3 mg/kg q8wk, dose increases with 100 mg possible Discontinuation rates Continuation rates 50% of all treatment discontinuations for safety issues occurred during first 2 years

59. 7 Year FU of Remicade in RA pts refractory to multiple DMARDs treatment: attrition and long-term effect Vander Cruyssen et al. Arthritis Res Ther. 2006;8(4):R112; Vander Cruyssen et al. EULAR 09 THU0181 Pts treated with IFX for 7 yrs experienced sustained clinical benefit - maintenance of low DAS and HAQ scores. Long term treatment with IFX is safe as most safety issues occurred during the first 2 years of IFX treatment and reveals no unexpected safety risks. 45.5% achieved DAS28 remission DAS 28 BL

60. RAISE survey

61. RA: Insights, Strategies and Expectations – Global Results of the RAISE Patient Need Survey Objectives The RAISE survey was designed to reveal the perceptions RA patients have of their disease and therapy Survey Size A total of 586 patients from 9 countries (8 EU + ) Patients were either on biologic therapy or biologic naïve but eligible for biologic treatment (= DAS28 >3.2 or an acute phase response, plus erosive disease and moderate-to-severe active RA) Patients characteristics Mean age at onset of RA symptoms: 41 years Average time to diagnosis of 3 years McInnes et al. EULAR 09 THU0206

62. RA: Insights, Strategies and Expectations – Global Results of the RAISE Patient Need Survey Product Features Impacting Willingness to Consider a New Biologic Biologic therapy has had significant impact on improving patients’ lives: For the majority of patients, biologic therapy had improved their symptoms and overall QoL compared with their previous non-biologic therapy Biologic users had significantly more ‘good’ days per month than biologic- naïve patients (71% vs 61%, respectively) In some biologic users: Emotional and/or physical help in preparing and/or administering SC injections is required Their biggest concern is injection site pain or irritation. McInnes et al. EULAR 09 THU0206

63. Agenda Spondyloarthropathies Early Rheumatoid Arthritis Established Rheumatoid Arthritis Benefit - Risk

64. Safety Abstracts: Stats by Molecule

65. Safety Abstracts: Topics Overview TopicsTotalanti-TNFABAADACZPETNIFXRTXTCZ Cardiovascular Diseases 17811111 Infections / TB 1581221 General + Competition 1141112 Malignancies 33 Male Fertility 22 Vaccines 211 Gastro 211 Anemia/Fatigue 22 Pregnancy 11 Liver Enzymes 11 Demyelinating Disease 11

66. Contraindications, Warnings and Precautions of TNFα inhibitors TNF  Inhibitors: EU Summary of Product Characteristics Infusion / injection reactions  /  Hypersensitivity/ allergy  Infections, TB*, Sepsis  Malignancies/ LymphomaCaution Congestive Heart failure* (NYHA class III/IV)  Autoimmune processes/ auto-antibodies  Neurological events  Haematologic reactions †  Hepatobiliary event  EMEA Product specific SPCs 2008. * contraindicated for adalimumab and infliximab, special warning for etanercept † special warning for adalimumab and etanercept

67. Remicade Educational Programs Aim: to educate physicians and other HCP on relevant information on a safe use of IFX, and monitor their awareness Infliximab: –Tuberculosis (TB): Patients should be evaluated with appropriate screening measures prior to initiation of infliximab therapy. Subjects who screen positive for latent TB should initiate treatment for latent TB prior to IFX therapy. Subjects treated with IFX have an increased risk for TB, so vigilance should be exercised in order to detect TB signs and symptoms. –Shortened infusions in RA: shortening the IFX infusion time (  1 hour) is restricted to patients with RA and should only be considered for those patients with RA on concomitant MTX therapy who have tolerated 3 or more IFX infusions administered over the currently recommended infusion time of  2 hours. –Pediatric Crohn’s disease: when prescribing IFX for pediatric CD patients, the physician should be aware of the need to assess TB risk prior to IFX treatment, the risk of: opportunistic infections (including TB), acute infusion-related and delayed hypersensitivity reactions, lymphoma and other malignancies, and the need for immunisations to be up-to-date IFX: infliximab; RA: rheumatoid arthritis; MTX: methotrexate; CD: Crohn’s disease Data on file, Centocor

68. Worldwide Patient Exposure since Launch: Therapeutic Area - Geography Post-marketing surveillance total treated patients 1,136,376 Worldwide Data on file, Centocor (PSUR 18, October 2008). 419,883 540,910 175,583 * EU includes Norway, ROW includes Japan and Canada Cumulative Since Launch: 24 Aug 1998-23 Aug 2008

69. British Society of Rheumatology Registry: Serious Infections with anti-TNF agents* *Serious Infection:‘Infection requiring hospitalisation, IV antibiotic treatement or leading to death‘ ** adjusted to baseline risk factors: age, sex, disease severity, co-morbidity, extra-articular manifestations, steroid use, smoking † No. of infections/Person-years 1.040.971.07 Ref value 255 / 4618 † 209 / 4075 † 61 / 1175 † 56 / 1352 † Rate of serious infections for anti-TNF agents compared to DMARDS Adjusted Incidence Rate Ratio ** Dixon WG, et al. Arthritis Rheum 2006;54:2368-2376.

70. Active treatmentFollow-up period 1 st 90 daysduration of Tx + 90 days Ever treatedReceiving of Tx time British Society of Rheumatology (BSR) Registry: Serious Infections with anti-TNF Agents Using Different Models 0.1 1 10 100 1 st 90 days of treatment currently receiving treatment Duration of treatment +90 days ever treated Adjusted incidence rate of Serious infections of anti-TNFs vs. DMARDS using various models. OR (95% CI) DMARDS Different models used, including varying lengths of follow up time Treatment period Model Registry Dixon WG, et al. Arthritis Rheum 2007;56:2896-2904.

71. Data from the German RABBIT Registry: Serious Infections with anti-TNF agents Listing et al. Arthritis Rheum 2005;52:3403-12 ** The patients receiving Biologics were more severe. RR was adjusted to baseline risk factors: age, number of DMARD failures, DAS28, CRP level, the presence of rheumatoid factor (RF), and disability. RR = 2.1 (0.8-5.5) 20/34631 / 51213 / 601 Rate of serious infections for anti-TNF agents compared to DMARDS RR = 2.2 (0.9-5.4)

72. Apoptosis Activation of T-cells Selectins Integrins Chemokines TNF Granuloma Migration of DC NO TNF  in Immunity to Mycobacterium Tuberculosis Granulomas = immunological strategy –for containing intracellular infections that cannot be eradicated by host defenses. Latent tuberculosis –Infection maintain in semi- dormant state –Requiring integrity of granulomas TNF is essential for the formation and maintenance of granulomas WHO active TB estimation –50 /100000 in Europe An estimated 1/3 of the world population has latent TB R Wallis et al Clinical Infectious Diseases 2005; 41:S194–8 Keane Rheumatology 2005; 44: 714-720 Theis et al; Aliment Pharmacol Ther 2008; 27: 19-30

73. TB Screening Is Effective in Reducing the Risk: EU and US Experience Feb 2000-Aug 2008 Post-marketing surveillance TB reporting rate per 1,000 patients Exposed In Period (EIP) EU/Norway = Europe and Norway Data on file, Centocor (PSUR 18, October 2008). Physicians must always be vigilant for TB or any infection regardless of the number of infusions Rate per 1,000 EIP Patients TB Education Program Initiated Three-level screening is most effective PPD / Pulm XRay / Past Medical History

74. Algorithm for TB Testing: European-Based Recommendations Treat active TB to resolution New patient office visit PPD test positive and active TB Initiate latent TB treatment Initiate therapy Administer appropriate TB screening test (PPD skin test + CXR + family history) Evaluate test results Test negative Initiate therapy PPD test positive and normal CXR Adapted from Arend SM et al. Netherlands J Med. 2003;61:111-119. Please consider your Local Guidelines where available

75. Malignancy Reporting Rates over Time Worldwide malignancy reporting rate per 1000 PYsfE* per PSUR interval Post-marketing surveillance Data on file, Centocor (PSUR 18, October 2008).*Patient Years since first Exposure

76. Malignancies- anti-TNF treated vs. Non-Anti-TNF treated RA Patients Adjusted Risk of all Malignancies reported for anti-TNFs vs. Non Biologics 1 Wolfe F & Michaud K. Arthritis Rheum. 2007;56(9):2886-95. 2 Askling J et al. EULAR 2007. Abstract OP0013. 3 Setoguchi S et al. Arthritis Rheum. 2006;54:2757-2764. Registries 1 2 3 12340.80.6 Relative Risk (95% CI) Study Populations RefNPt Years FU 113,001~ 49,000 25,40114,261 31,1522,940 ref

77. Lymphoma Reporting Rates Over Time Post-marketing surveillance Data on file, Centocor (PSUR 18, October 2008). Worldwide lymphoma reporting rate per 1,000 PYsfE* per PSUR interval *Patient Years since first Exposure Cumulative Reporting Rate since first exposure: 0.17

79. Snoeckx et al. EULAR 09 OP-0156 Update On Pregnancy Outcomes In Women Taking Infliximab: The IFX Safety Database J&J Worldwide Safety Database of spontaneously reported AEs (through Aug 2008); data for 723 of 1,406 pregnancies with maternal IFX exposure - No IFX-exposed offspring met the VATER (VACTERL) criteria - Due to the limited data, IFX should be used during pregnancy only if clearly needed

80. Remicade Benefit:Risk - Conclusions Remicade, with 7 approved indications, is the most widely used TNF  inhibitor –More than 15 years of safety data collected in clinical trials –Estimated exposure since commercial launch on 24 August 1998 >1.1 million patients >4.2 million patient-years since first exposure Remicade is effective in patients with inflammatory diseases who have failed conventional therapies in RA, AS, PsA, Pso, CD, Ped CD, and UC When given to appropriately selected patients, Remicade’s benefit-risk profile continues to be favorable Data on file, Centocor (PSUR 18, October 2008).