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International Literature Search in Rheumatology

International Literature Search in Rheumatology. Vol. 6, Number 2 December 2011 In this issue: Highlights of the 2011 Annual Meeting of the American College of Rheumatology November 5-9, Chicago, IL. Table of Contents. Author(s) Poster / presentation #s Slides

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International Literature Search in Rheumatology

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  1. International Literature Search in Rheumatology Vol. 6, Number 2 December 2011 In this issue:Highlights of the 2011 Annual Meeting of theAmerican College of RheumatologyNovember 5-9, Chicago, IL

  2. Table of Contents Author(s) Poster / presentation #s Slides Hørslev-Petersen K 394 3 – 10 Genovese M 401 11 – 18 Genovese M 402 19 – 26 VanVollenhoven R 408 27 – 34 Yonemoto Y 1236 35 – 42 Yazici Y 124043 – 50 Bakker M 1695 51 – 58 O'Dell J 169659 – 66 Kaine JL 2190 67 – 74 Roussy J-P 2193 75 – 82 Meissner B 2197 83 – 90 Dirven L 2200 91 – 98 Raaschou P 2523 99 – 106 Galloway J 2524 107 – 114 Mercer L 2525 115 – 122

  3. Adalimumab Added to Methotrexate andIntra-Articular Glucocorticoid Increases Remission Rates At One Year In Early,DMARD-Naïve Patients with Rheumatoid Arthritis - An Investigator-Initiated Randomized, Controlled, Double-Blinded Study Hørslev-Petersen K, et al: Presented at ACR 2011; Poster #394

  4. Adalimumab + Methotrexate & Intra-articular Glucocorticoid in DMARD-naïve, Early RA • Objective: To assess the efficacy and safety of adding adalimumab (ADA) to methotrexate (MTX) and intra-articular glucocorticoid • Subjects: 180 DMARD-naïve RA patients, disease duration < 6 months • Methodology: • Subjects were randomized to MTX 7.5 mg weekly + ADA 40 mg every other week or MTX + placebo • All patients had triamcinolone injections into swollen joints at weeks 0, 4, 8, and 12, then every third month up to 12 months • If DAS28 > 3.2 at 3 months, sulfasalazine & hydroxychloroquine were added • Assessments: DAS28 (CRP), SDAI and ACR/EULAR remission criteria • Primary outcome: Frequency of DAS28 (CRP) < 3.2 Adapted from Hørslev-Petersen K, et al: Presented at ACR 2011; Poster #394

  5. Adalimumab + Methotrexate & Intra-articular Glucocorticoid in DMARD-naïve, Early RA: Baseline Characteristics Adapted from Hørslev-Petersen K, et al: Presented at ACR 2011; Poster #394

  6. Adalimumab + Methotrexate & Intra-articular Glucocorticoid in DMARD-naïve, Early RA: Treatment Characteristics During the Study Adapted from Hørslev-Petersen K, et al: Presented at ACR 2011; Poster #394

  7. Adalimumab Added to MTX & I.A. Glucocorticoid: DAS28 < 3.2 at 12 Months 100% p = 0.74 84 81 80% 60% % of patients with DAS28 < 3.2 40% 20% 0% MTX + Placebo MTX + Adalimumab Adapted from Hørslev-Petersen K, et al: Presented at ACR 2011; Poster #394

  8. Adalimumab Added to MTX & I.A. Glucocorticoid: Remission 100% MTX + Placebo p = 0.059 MTX + Adalimumab 78 80% p = 0.0017 64 63 p = 0.0235 p = 0.0095 60% 49 48 % of patients 38 40% 31 28 20% 0% DAS28 < 2.6 SDAI < 3.3 ACR/EULARremission(28 joint) ACR/EULARremission(40 joint) Adapted from Hørslev-Petersen K, et al: Presented at ACR 2011; Poster #394

  9. Adalimumab + Methotrexate & Intra-articularGlucocorticoid in DMARD-naïve, Early RA: Conclusions • In DMARD-naïve patients with early RA, excellent disease control was achieved by a targeted step-up strategy using methotrexate and intra-articular glucocorticoid injections • Addition of adalimumab to methotrexate and intra-articular glucocorticoid improved the remission rates considerably • The treatments were well tolerated Adapted from Hørslev-Petersen K, et al: Presented at ACR 2011; Poster #394

  10. Adalimumab + Methotrexate & Intra-articular Glucocorticoid in DMARD-naïve, Early RA Commentary from International Literature Search in Rheumatology’s Canadian Editorial Panel • This study used methotrexate doses of 20 mg per week, which reflects current practice in Canada; the use of intra-articular injections also applies to rheumatology standard-of-care in Canada • This study is, therefore, very applicable in our context • The only issue is availability of biologics in very early disease, but this study helps to corroborate the need for early treatment with biologics in RA Commentary on Hørslev-Petersen K, et al: Presented at ACR 2011; Poster #394

  11. One Year Efficacy and Safety Results of a Phase II Trial of Secukinumab in Patients with Rheumatoid Arthritis Genovese MC, et al: Presented at ACR 2011; Poster #401

  12. Phase II Study of Secukinumab in Rheumatoid Arthritis • Objective: To assess the efficacy and safety of secukinumab in patients with active RA despite stable MTX • Subjects: 237 adults with RA, taking MTX therapy • Methodology: • Subjects were randomized to receive monthly s.c. secukinumab25 mg, 75 mg, 150 mg, 300 mg or placebo • After Week 16, dose adjustments were made if necessary and placebo patients were switched to active therapy • Primary endpoint: ACR 20 at week 16 (previously reported) • Key efficacy measures evaluated in this analysis: Long-term results from week 24 to week 52 • No placebo arm during this period: all patients were receiving secukinumab Adapted from Genovese MC, et al: Presented at ACR 2011; Poster #401

  13. Secukinumab for Rheumatoid Arthritis: Study Design Week 0 randomization N=237 25 mgN=54 75 mgN=49 150 mgN=43 300 mgN=41 pboN=50 Re-assignment at Week 16 based on ACR20 response: R and NR N=47 N=47 N=43 N=38 N=45 Patients available for evaluation at Week 52 25/25 R=18 25/150 NR=27 75/75 R=23 75/150 NR=23 150/150 R=20 150/300 NR=23 300/300 R=21 300/300 NR=16 pbo/150 R=18 pbo/150 R=17 R: Responder; NR: Non-Responder; pbo: Placebo; N: Number of patients; Wk: Week; MTX: Methotrexate Adapted from Genovese MC, et al: Presented at ACR 2011; Poster #401

  14. Secukinumab for Rheumatoid Arthritis: ACR and DAS28 Responses • Responders who remained on secukinumab 150 mg showed further improvement in ACR50 and ACR70 over time up to week 52 • Placebo patients who were responders by week 16 also had high ACR50 and ACR70 response rates by week 52 • DAS28 (CRP) reductions were sustained through week 52 in responders across dose groups, with lowest responses in those who remained on 25 mg throughout the trial Adapted from Genovese MC, et al: Presented at ACR 2011; Poster #401

  15. Secukinumab for Rheumatoid Arthritis: Discontinuations 50% Overall study discontinuations Discontinuations for AEs Discontinuations for Unsatisfactory therapeutic effects 38.9 40% 30.0 30% 24.4 % of patients 22.4 20% 14.8 14.0 13.0 12.0 9.8 10% 8.2 7.0 6.0 4.9 4.1 0.0 0% 25 mg 75 mg 150 mg 300 mg Total Adapted from Genovese MC, et al: Presented at ACR 2011; Poster #401

  16. Secukinumab for Rheumatoid Arthritis: Adverse Events 100% 25 mg 75 mg 150 mg 300 mg 80% Total 68.3 65.2 64.8 63.5 61.1 60% % of patients 40% 34.8 33.3 31.9 28.3 26.1 20% 0% Overall AEs Infections / infestations Adapted from Genovese MC, et al: Presented at ACR 2011; Poster #401

  17. Phase II Study of Secukinumab in Rheumatoid Arthritis: Conclusions • The primary efficacy endpoint was not achieved in this trial • ACR20 responders at Week 16 experienced maintenance or improvement of efficacy through week 52 with highest efficacy in patients who remained on secukinumab 150 mg throughout the trial • DAS28 and HAQ scores improved through week 52 in responders who remained on secukinumab 150 mg • Patients on secukinumab who were non-responders at week 18 did not gain much additional efficacy benefit through week 52 after dose escalation • Infection was the most frequently reported adverse event, with nasopharyngitis and pharyngitis reported most commonly • The rate of adverse events, including infections, was not dose dependent Adapted from Genovese MC, et al: Presented at ACR 2011; Poster #401

  18. Phase II Study of Secukinumab in Rheumatoid Arthritis Commentary from International Literature Search in Rheumatology’s Canadian Editorial Panel • The success of biologic agents for the treatment of RA over the past 10 years has generated ongoing research to find drugs that target new pathways • A Phase 2 study previously reported that targeting IL-17 with secukinumab did not achieve its primary endpoint at week 16 • This paper reports further data up to 1 year from that study and shows that although the group that did respond maintained their response, those who were non-responders did not improve with dose escalation • As reported elsewhere at this meeting, there are positive data treating spondyloarthropathies with this agent, particularly ankylosing spondylitis, but it remains to be seen whether targeting IL-17 will turn out to be a useful addition to treat RA Commentary on Genovese MC, et al: Presented at ACR 2011; Poster #401

  19. Subcutaneous (SC) Abatacept (ABA) Versus Intravenous (IV) ABA in Patients (pts) with Rheumatoid Arthritis: Long-Term Data From the ACQUIRE (Abatacept Comparison of Sub[QU]cutaneous versus Intravenous in Inadequate Responders to MethotrexatE) Trial Genovese MC, et al: Presented at ACR 2011; Poster #402

  20. Subcutaneous vs. Intravenous Abataceptin RA: Long-term Data (ACQUIRE study) • Objective: To evaluate the efficacy and safety of the subcutaneous (SC) formulation of abatacept compared to the intravenous (IV) formulation over 24 months • Subjects:1372 patients from the ACQUIRE study • Methodology: Long-term extension (LTE) study of the ACQUIRE trial • In the initial 6-month study, SC abatacept (125 mg/week) and IV abatacept showed comparable safety and efficacy • After 6 months, patients could enter the LTE and receive SC abatacept 125 mg/week for an additional 18 months • LTE assessments: safety, immunogenicity, efficacy Adapted from Genovese MC, et al: Presented at ACR 2011; Poster #402

  21. ACQUIRE Study Long-term Extension: Baseline Characteristics Adapted from Genovese MC, et al: Presented at ACR 2011; Poster #402

  22. ACQUIRE Study Long-term Extension: Efficacy – ACR 20/50/70 Over 24 Months All patients switch to SC abatacept SC abatacept 100.0 IV abatacept switched to SC abatacept 80.0 ACR 20 60.0 Patients achieving ACR response (%) ACR 50 40.0 ACR 70 20.0 0.0 0 29 85 141 253 365 449 533 617 729 15 57 113 169 Visit day Adapted from Genovese MC, et al: Presented at ACR 2011; Poster #402

  23. ACQUIRE Study Long-term Extension: Efficacy – LDAS and DAS28 Remission All patients switch to SC abatacept SC abatacept 100.0 IV abatacept switched to SC abatacept 80.0 60.0 Patients achieving ACR response (%) LDAS 40.0 DAS28-definedremission 20.0 0.0 0 29 85 141 253 365 449 533 617 729 15 57 113 169 Visit day Adapted from Genovese MC, et al: Presented at ACR 2011; Poster #402

  24. ACQUIRE Study Long-term Extension: Safety Adapted from Genovese MC, et al: Presented at ACR 2011; Poster #402

  25. ACQUIRE Study Long-term Extension: Conclusions • Over 24 months, subcutaneous abatacept showed acceptable safety, with high patient retention, similar to the IV experience • Efficacy was comparable between SC and IV groups • ACR and HAQ responses and DAS28 remission rates were maintained in the LTE Adapted from Genovese MC, et al: Presented at ACR 2011; Poster #402

  26. Subcutaneous vs. Intravenous Abatacept in RA: Long-term Results Commentary from International Literature Search in Rheumatology’s Canadian Editorial Panel • In this trial, patients with relatively longstanding RA (8 years) did well on either i.v. or s.c. abatacept, with similar retention, efficacy and safety in both groups • It remains to be seen whether patients who are currently receiving i.v .abatacept monthly will be interested in switching to weekly s.c. dosing, but this study does provide reassurance that, for those who wish to make the switch, the medication is effective Commentary on Genovese MC, et al: Presented at ACR 2011; Poster #402

  27. Tofacitinib (CP-690,550), An Oral Janus Kinase Inhibitor, or Adalimumab Versus Placebo in Patients with Rheumatoid Arthritis on Background Methotrexate:A Phase 3 Study van Vollenhoven RF, et al: Presented at ACR 2011; Poster #408

  28. Tofacitinib vs. Adalimumab or Placebo in RA Patients on Methotrexate • Objective: To compare the efficacy and safety of tofacitinib to adalimumab and to placebo in active RA • Subjects: 717 patients with active RA and inadequate response to methotrexate • Methodology: • Subjects were randomized (4:4:4:1:1 ratio) to: • Tofacitinib 5 mg BID SC Q2W); • Tofacitinib 10 mg BID SC Q2W; • Adalimumab 40 mg SC Q2W; • Placebo  tofacitinib 5 mg BID SC Q2W; or • Placebo  tofacitinib 10 mg BID SC Q2W • Efficacy assessments: ACR response, HAQ-DI, DAS28 • Safety was also evaluated Adapted from van Vollenhoven RF, et al: Presented at ACR 2011; Poster #408

  29. Tofacitinib vs. Adalimumab or Placebo in RA: ACR20 Responses at Month 6 100% 80% 60% 52.6 51.5 % of patients 47.2 40% 28.3 20% 0% Adalimumab 40 mg Tofacitinib 5 mg Tofacitinib 10 mg Placebo All comparisons of active therapies vs. placebo were statistically significant (p<0.001) Adapted from van Vollenhoven RF, et al: Presented at ACR 2011; Poster #408

  30. Tofacitinib vs. Adalimumab or Placebo in RA Patients: DAS28 Remission at Month 6 14% 12.5 12% 10% 8% 7.3 % of patients 6.2 6% 4% 2% 1.1 0% Adalimumab 40 mg Tofacitinib 5 mg Tofacitinib 10 mg Placebo All comparisons of active therapies vs. placebo were statistically significant (p<0.05) Adapted from van Vollenhoven RF, et al: Presented at ACR 2011; Poster #408

  31. Tofacitinib vs. Adalimumab or Placebo in RA Patients: Mean HAQ Change at Month 6 Adalimumab 40 mg Tofacitinib 5 mg Tofacitinib 10 mg Placebo 0 -0.1 -0.2 -0.24 -0.3 Change in HAQ Score from baseline -0.4 -0.5 -0.49 -0.55 -0.6 -0.61 -0.7 All comparisons of active therapies vs. placebo were statistically significant (p<0.0001) Adapted from van Vollenhoven RF, et al: Presented at ACR 2011; Poster #408

  32. Tofacitinib vs. Adalimumab or Placebo in RA Patients on Methotrexate: Adverse Events Adapted from van Vollenhoven RF, et al: Presented at ACR 2011; Poster #408

  33. Tofacitinib vs. Adalimumab or Placebo in RA Patients on Methotrexate: Conclusions • Tofacitinib demonstrated rapid, significant, and clinically meaningful reductions in signs and symptoms of RA and improvements in physical function • No new tofacitinib safety signals were detected • Efficacy results with tofacitinib and adalimumab (both given on MTX background) were similar Adapted from van Vollenhoven RF, et al: Presented at ACR 2011; Poster #408

  34. Tofacitinib vs. Adalimumab or Placebo in RA Patients on Methotrexate Commentary from International Literature Search in Rheumatology’s Canadian Editorial Panel • Tofacitinib will be a useful addition to our armamentarium for the treatment of RA, especially as it is an oral medication • The SAEs are, however, of some concern; larger studies should be carried out to further assess this Commentary on van Vollenhoven RF, et al: Presented at ACR 2011; Poster #408

  35. Direct Comparison of Four Biologics in Biologic-naïve Rheumatoid Arthritis Patients Yonemoto Y, et al: Presented at ACR 2011;Poster #1236

  36. Direct Comparison of Four Biologics in Biologic-naïve RA • Objective: To compare treatment response to four biologics in biologic-naïve RA patients in a real-life, clinical setting • Subjects: 142 biologic-naïve RA patients who were started on a biologic • Infliximab (n=37) • Etanercept (n=39) • Tocilizumab (n=27) • Adalimumab (n=39) • Methodology: • A number of variables were analyzed at baseline and at six months: ESR, CRP, MMP-3, SJC/TJC, DAS28-ESR • Drug survival rate was also assessed Adapted from Yonemoto Y, et al: Presented at ACR 2011; Poster #1236

  37. Direct Comparison of Four Biologics: Baseline Characteristics Adapted from Yonemoto Y, et al: Presented at ACR 2011; Poster #1236

  38. Direct Comparison of Four Biologics:DAS28-ESR Scores at 6 Months 6.0 5.0 4.0 3.0 DA28-ESR 2.0 1.0 0 Biologic: IFX ETN TCZ ADA Baseline DAS28-ESR: 4.9 4.8 5.5 4.8 Adapted from Yonemoto Y, et al: Presented at ACR 2011; Poster #1236

  39. Direct Comparison of Four Biologics: MMP-3 at 6 Months 1200.0 1000.0 800.0 MMP-3 (ng/ml) 600.0 400.0 200.0 0.0 Biologic: IFX ETN TCZ ADA Baseline MMP-3 (ng/mL): 275.2 241.0 315.4 286.0 Adapted from Yonemoto Y, et al: Presented at ACR 2011; Poster #1236

  40. Direct Comparison of Four Biologics: Drug Survival Rates at 6 Months 100 100% 92 89 89 80% 60% % still taking drug at 6 months 40% 20% 0% Infliximab Etanercept Tocilizumab Adalimumab No significant difference between biologics in drug survival rates Adapted from Yonemoto Y, et al: Presented at ACR 2011; Poster #1236

  41. Comparison of Four Biologics in Biologic-naïve RA: Conclusions • In this study, there was a larger fall in MMP-3 with tocilizumab than with the other two agents • The study suggests that tocilizumab may provide therapeutic efficacy at least comparable to TNF inhibitors in biologic-naïve RA patients Adapted from Yonemoto Y, et al: Presented at ACR 2011; Poster #1236

  42. Direct Comparison of Four Biologics in Biologic-naïve RA Commentary from International Literature Search in Rheumatology’s Canadian Editorial Panel • This confirms that all the TNF inhibitors are equally clinically effective and that tocilizumab is at least as effective in biologic-naïve RA patients Commentary on Yonemoto Y, et al: Presented at ACR 2011; Poster #1236

  43. Comparative Efficacy and Tolerability of Biologic Therapies in Early Rheumatoid Arthritis Utilizing a Bayesian Approach Yazici Y, et al: Presented at ACR 2011;Poster #1240

  44. Comparative Efficacy and Tolerability of Biologic Therapies in RA • Objective: To determine the relative efficacy and tolerability of biologic agents approved for the treatment of MTX-naïve early RA • Methodology: Agents were compared using an indirect approach (mixed treatment comparison [MTC]) • Systematic literature review identified RCTs that measured efficacy and safety endpoints in MTX-naïve, early RA with: • Abatacept, adalimumab, etanercept, golimumab, and infliximab • Assessments: ACR20/50/70, DAS28 remission, SAEs, serious infections and withdrawals at 1 year Adapted from YaziciY, et al: Presented at ACR 2011; Poster #1240

  45. Comparative Efficacy of Biologic Therapies in RA: Efficacy Measures Adapted from Yazici Y, et al: Presented at ACR 2011; Poster #1240

  46. Comparative Efficacy of Biologic Therapies in RA: Odds Ratios for ACR Responses and DAS28 Remission Fixed-effects model Odds Ratios (Log Scale) Random-effects model 0.1 1 10 100 ETN 50mg ETN 50mg ETN 50mg ETN 50mg 3.02 ADA 40mg ADA 40mg ADA 40mg ADA 40mg 1.60 ACR 70 ACR 50 DAS-R ACR 20 ABA 10mg/kg ABA 10mg/kg ABA 10mg/kg ABA 10mg/kg 1.96 GOL 50mg GOL 50mg GOL 50mg GOL 50mg 1.64 INF 3mg/kg INF 3mg/kg INF 3mg/kg INF 3mg/kg 1.44 2.59 2.37 2.52 1.92 2.19 2.84 1.84 1.98 2.34 1.60 1.63 1.71 1.53 1.80 1.77 Adapted from Yazici Y, et al: Presented at ACR 2011; Poster #1240

  47. Comparative Tolerability of Biologic Therapies in RA: Serious Infections and Serious AEs Fixed-effects model Odds Ratios vs. Placebo + MTX Random-effects model 0.01 0.1 10 100 1 ETN 50mg 0.94 ABA 10mg/kg SeriousInfections 0.99 GOL 50mg 0.91 INF 3mg/kg 1.32 ETN 50mg 0.59 ADA 40mg 1.26 SeriousAE ABA 10mg/kg 0.45 GOL 50mg 0.63 INF 3mg/kg 2.97 Adapted from Yazici Y, et al: Presented at ACR 2011; Poster #1240

  48. Comparative Tolerability of Biologic Therapies in RA: Discontinuations Fixed-effects model Odds ratios vs. Placebo + MTX Random-effects model 0.01 0.1 10 100 1 ETN 50mg 0.57 ADA 40mg 0.61 AnyWithdrawal ABA 10mg/kg 0.90 GOL 50mg 0.76 INF 3mg/kg 0.85 ETN 50mg 0.78 ADA 40mg 1.71 Withdrawaldue to AE ABA 10mg/kg 0.70 GOL 50mg 2.66 INF 3mg/kg 3.32 Adapted from Yazici Y, et al: Presented at ACR 2011; Poster #1240

  49. Comparative Efficacy of Biologic Therapies in RA: Conclusions • In general, all biologic agents used in MTX-naïve early RA demonstrated similar efficacy and tolerability • Except for infliximab, which appeared to have less favorable efficacy and tolerability • For specific outcomes studied, etanercept and abatacept were not significantly different from each other and were the only biologics that did not demonstrate a significantly decreased likelihood of efficacy or tolerability compared with any of the other agents Adapted from Yazici Y, et al: Presented at ACR 2011; Poster #1240

  50. Comparative Efficacy and Tolerability of Biologic Therapies in RA Commentary from International Literature Search in Rheumatology’s Canadian Editorial Panel • All of the biologics analyzed in this Bayesian analysis were comparable with regards to efficacy and safety in an ERA, MTX-naïve population • However, only etanercept and abatacept did not show any decreased likelihood of efficacy or tolerability compared to other agents Commentary on Yazici Y, et al: Presented at ACR 2011; Poster #1240

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