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Biomarkers and predictors of responsiveness to biologics in RA

Biomarkers and predictors of responsiveness to biologics in RA. Professor John Isaacs Professor of Clinical Rheumatology Newcastle University Newcastle, UK. What evidence is available that response to therapy can be predicted?. TNF inhibitors Rituximab.

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Biomarkers and predictors of responsiveness to biologics in RA

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  1. Biomarkers and predictors of responsiveness to biologics in RA Professor John Isaacs Professor of Clinical RheumatologyNewcastle UniversityNewcastle, UK

  2. What evidence is available that response to therapy can be predicted? TNF inhibitors Rituximab

  3. Predictors of responsiveness to TNF inhibitors Clinical factors Serological biomarkers Genetic biomarkers

  4. Clinical factors that predict responsiveness to TNF inhibitors • n=2879 (1267 ETA, 1612 INF) • Poorer response • higher baseline HAQ • current smoker (INF, OR 0.77 [CI 0.60–0.99]) • Better response: • current use of NSAIDs • current use of MTX (ETA, OR 1.82 [CI 1.38–2.40])

  5. RF, anti-CCP and genetic variants: Association with response to TNF inhibitors • n=642 (278 ETA, 296 INF, 68 ADA) • RF and anti-CCP negativity associated with better response • SE, PTPN22 status not associated with response • Females less likely to achieve remission Potter C et al. Ann Rheum Dis. 2009;68:69-74. Epub 2008 Mar 28

  6. Autoantibodies in TNF inhibitor treated RA patients Analyses were performed in 521 patients for whom serum samples were available. p-values stated are for linear regression, adjusted for concurrent DMARD, gender, baseline HAQ and DAS28 score. Potter C et al. Ann Rheum Dis. 2009;68:69-74. Epub 2008 Mar 28

  7. Response to TNF inhibitors may decline with increasing anti-CCP titre • 236 etanercept patients • CCP –ve = <50 u/mL; CCP +ve = >50 u/mL <1600 u/mL; CCP high +ve = >1600 u/mL • CCP high = 27% of population Etanercept EULAR responses according to CCP status 90 80 70 60 EULAR no response Patients (%) 50 EULAR response 40 30 20 10 0 CCP -ve CCP +ve CCP high +ve Drynda S et al. ACR 2008

  8. Genetic factors in anti-TNF treatment response • Results are inconsistent and inconclusive • Small sample sizes and limited power (n=50–300) • Varied designs (e.g. TNF inhibitor, disease, outcome) • Investigate individual polymorphisms

  9. Example: TNF-308 promoter SNP * Performed multivariate and haplotype analyses † Meta-analysis incorporating 6 additional studies ‡ Study involved RA, PsA and AS

  10. Predictors of responsiveness to rituximab • Serological biomarkers – learnings from: • The DANCER study • The REFLEX study

  11. Dose-ranging Assessment: iNternational Clinical Evaluation of Rituximab in RA (DANCER) Emery et al 2006. Arth Rheum 2005:54;1390-400

  12. DANCER study: ACR responses at 6 months – RF +ve vs RF -ve patients, ITT RF positive RF negative Roche, data on file

  13. DANCER study: Placebo-adjusted ACR responses at 6 months – RF +ve vs RF -ve patients 30 24 25 21 20 16 15 15 Patients (%) 10 6 5 0 Rituximab 2 x 1000 mg (n=122) Rituximab 2 x 1000 mg (n=63) -5 -4 -10 ACR20 ACR50 ACR70 RF positive RF negative Roche, data on file

  14. A Randomised Evaluation oFLong-term Efficacy of rituXimab in RA (REFLEX) Cohen S et al. Arthritis Rheum 2006:54;2793-806

  15. REFLEX study: ACR responses at Week 24 in RF+ve vs RF-ve patients (ITT) RF positive (ITT) RF negative (ITT) p<0.0001 54 p<0.0009 41 p<0.0001 29 NS 19 p<0.0001 17 p=0.045 13 12 9 6 5 2 0 ACR20 ACR50 ACR70 ACR20 ACR50 ACR70 ACR20 ACR50 ACR70 ACR20 ACR50 ACR70 Placebo (n=160) Rituximab 1000 mg x 2 (n=160) Placebo (n=41) Rituximab 1000 mg x 2 (n=64) Cohen et al, 2006; Smolen et al. 2006

  16. REFLEX study: Placebo-adjusted ACR responses at Week 24 in RF+ve vs RF-ve patients (ITT) RF positive (ITT) RF negative (ITT) Patients (%) Rituximab 1000 mg x 2 (n=234) Rituximab 1000 mg x 2 (n=64) Cohen et al, 2006; Smolen et al. 2006

  17. REFLEX study: ACR responses at Week 24 according to RF and anti-CCP status ACR20 ACR50 ACR70 RF and/or anti-CCP positive RF negative and anti-CCP negative Patients (%) ACR20 ACR50 ACR70 ACR20 ACR50 ACR70 ACR20 ACR50 ACR70 ACR20 ACR50 ACR70 Placebo (n=107) Rituximab (n=157) Placebo (n=16) Rituximab (n=29) Tak et al, ACR 2006

  18. REFLEX study: Placebo-adjusted ACR responses at Week 24 according to RF and anti-CCP status RF and/or anti-CCP positive RF negative and anti-CCP negative Patients (%) Rituximab (n=157) Rituximab (n=29) Cohen et al, 2006; Smolen et al. 2006

  19. REFLEX Study: 56 week radiographic outcomes: seropositive subgroups RF and/or anti-CCP positive RF negative and anti-CCP negative P=0.0085 P=0.0225 P =0.0018 Roche, data on file

  20. Summary Conflicting reports of association between TNF polymorphisms and clinical response to TNF inhibitors Rituximab shows consistent association with RF and/or anti-CCP as the biomarkers predictive of clinical response RA patients who are seropositive (RF+ and/or anti-CCP+) appear to have an enriched response to rituximab

  21. The FUTURE Data from SERENE, MIRROR and IMAGE studies of rituximab will provide an additional opportunity to assess serological biomarker association with clinical response Further studies of biomarkers with the range of biological therapies are warranted to fully assess their potential role in predicting response

  22. What does this mean for Ed’s patient? Seropositivity suggests a better outcome with rituximab

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