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Con arguments: Maxime DOUGADOS

House position: «  Following an inadequate response to a first TNF inhibitor, switching to rituximab is a more effective option than cycling between TNF inhibitors ». Con arguments: Maxime DOUGADOS

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Con arguments: Maxime DOUGADOS

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  1. House position: « Following an inadequate response to a first TNF inhibitor, switching to rituximab is a more effective option than cycling between TNF inhibitors» Con arguments: Maxime DOUGADOS Paris-Descartes University, Medicine Faculty; UPRES-EA 4058; AP-HP, Cochin Hospital; Rheumatology B Dept; PARIS, France

  2. House position: « Following an inadequate response to a TNF inhibitor, switching to rituximab is a more effective option than cycling between TNF inhibitors»

  3. Different TNF agents • Soluble receptor: - Etanercept • Monoclonal antibodies: - Infliximab - Adalimumab - Certolizumab - Golimumab - …

  4. TNF1 TNF1 TNF1 TNF5 TNF5 TNF5 TNF2 TNF2 TNF2 TNF4 TNF4 TNF4 TNF3 TNF3 TNF3 TNF1 TNF1 TNF5 TNF5 TNF2 TNF2 TNF4 TNF4 TNF3 TNF3

  5. TNF1 TNF1 TNF5 TNF5 TNF2 TNF2 TNF4 TNF4 TNF3 TNF3 Cycling No cycling

  6. The evidence • Observational studies Systematic literature research • Randomised controlled trials The example of Golimumab

  7. The evidence • Observational studies Systematic literature research • Randomised controlled trials The example of Golimumab

  8. Meldine, Cochrane, Embase databases up to december 2008 Keywords: « rheumatoid arthritis » AND « failure OR switching » AND « TNF inhibitors OR adalimumab OR etanercept OR « infliximab ». Citations identified for screening: 194 Observational studies* Citations excluded: 170 Reviews: 57 Not rheumatoid arthritis: 38 Not TNF inhibitor: 18 No efficacy outcome: 40 No switch: 17 Full publications included: 24 Full text excluded: 1 No differentiation one or two previous TNF inhibitor: 1 Hand search: 4 Abstracts: 5 Studies assessed: 32; 4434 patients Switch for lack of efficacy: 18 studies; 1826 pts Switch for adverse events: 10 studies;864 pts Switch for unknown reason: 13 studies;1528 pts *Remy A, …, Combe B. Personal communication, submitted EULAR 2009

  9. Observational studies* Switch for adverse events Switch for lack of efficacy % success % success Criteria N studies 9 8 7 12 N patients 1003 967 954 1183 Criteria N studies 4 5 5 6 N patients 335 372 372 451 *Remy A, …, Combe B. Personal communication, submitted EULAR 2009

  10. The evidence • Observational studies Systematic literature research • Randomised controlled trials The example of Golimumab

  11. Golimumab 100 mgn=153 Randomised controlled trial: the example of Golimumab Study design Phase 3, multi-center, randomized, double-blind, placebo-controlled, 3-arm study Subjects with active RA who were previously treated with one or more TNF inhibitor(s) (n=461). ~78% on DMARDs (MTX, SSZ, PLQ) Placebon=155 Golimumab 50 mgn=153 SQ injection Week 0 Week 4 Week 8 Double-blindedEarly Escape(GLM 50 mg) Double-blindedEarly Escape(GLM 100 mg) Double-blindedEarly Escape(No change) Week 12 Week 14* Week 16† Week 20 Week 24 Primary Endpoint: *ACR20 response at Week 14 †At Week 16, any patient with <20% improvement from baseline in both swollen and tender joint count had to enter early escape in a double-blinded fashion

  12. Randomised controlled trial: the example of Golimumab Prior Anti-TNFα Therapy *Subjects may have had more than 1 reason for discontinuing prior TNF-blocker therapy**Other includes non-efficacy related reasons, such as intolerance, financial, etc

  13. Randomised controlled trial: the example of Golimumab ACR20 Responders at week 24 by reason for discontinuing prior TNF inhibitor(s) Lack of Efficacy Intolerance or Other % Patients p=0.015 p<0.001 p=0.014 p=0.003 (n=96) (n=84) (n=89) (n=90) (n=81) (n=88)

  14. GolimumabWeek 24 AbataceptWeek 241 RituximabWeek 242 D=20 D=22 D=16 % Patients p<0.0001 p<0.0001 p<0.005 Pbo +MTX(n=90) GLM Combo+ MTX(n=194) Pbo + DMARDs(n=133) 10 mg/kg + DMARDs (n=256) Pbo + MTX(n=201) 1000 mg + MTX(n=298) Randomised controlled trial: the example of Golimumab ACR50 Response at week 24 compared with other biologics 1Genovese MC, et al. ACR 2005. Abstract 2772Cohen SB, et al. Arthritis Rheum 2006;54:2793-806 (92% of patients had inadequate efficacy of anti-TNF)

  15. GolimumabCombined OddsRatio Placebo (95% CI) p-value n (%) n (%) DMARD 107 Yes (1.8, 5.4) <0.0001 215 40 3 17.8 48 No (0.8, 4.2) 0.1836 29.2 1.8 89 18.8 No. of prior TNF inhibitor 90 1 (1.4, 4.5) 0.0021 -38.5 213 2.5 -20 44 2 (1.3, 8.3) 0.0141 -38 3.2 71 -15.9 21 3 (0.2, 5.3) 0.951 -13.6 0.9 22 -14.3 Reason for discontinuationof prior TNF inhibitor 96 (1.6, 5.5) 0.0004 39.3 173 3 17.7 Lack of efficacy 84 Non-efficacy related reasons (1.1, 3.8) 0.0265 162 34 2 20.2 Randomised controlled trial: the example of Golimumab Proportion of ACR20 responders at Week 14 by sub-group Proportion of ACR20 Responders at Week 14 Odds Ratio and 95% CIGolimumab Combined vs. Placebo * ** PlaceboBetter Golimumab combinedBetter *means GLM as the 2nd antiTNF **means GLM as the 3rd antiTNF Smolen et al, at EULAR 2008. Permission given by J. Smolen

  16. Conclusions (1/3) Switching from a first anti-TNF to a second one is of benefit for the patients.

  17. Conclusions (2/3) « Cycling » is fine but we must further evaluate … the wheel...

  18. Other biotherapy Open questions concerning the « wheel » • When to leave the wheel? • Possibility to re-enter in the wheel?

  19. Conclusions (3/3) First TNF failure Rituximab Second TNF Success Failure Success Failure ..but B cell depleted Other biologics Risks of other biotherapy?

  20. House position: « Following an inadequate response to a first TNF inhibitor, switching to rituximab is a more effective option than cycling between TNF inhibitors » Based on both the evidence and the experience, … the house position is not the optimal one

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