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Who likes doughnuts?      Gavin Giovannoni    Barts and The London
Or do you prefer bagels?
Guidelines for the prescribing of IFN-beta and GAFulfil the following 4 criteria:    1.   Able to walk independently    2....
Guidelines for the prescribing of NatalizumabNatalizumab is recommended as an option for thetreatment only of rapidly evol...
Definition of a disabling relapseThere is no accepted definition of a disabling relapse; the following is aworking definit...
Guidelines for the prescribing of FingolimodFingolimod is recommended as an option for the treatment of highly activerelap...
The relapsing MS DMT doughnut
The relapsing MS DMT doughnut         Highly active RRMS       Suboptimal responders ?               Active               ...
The relapsing MS DMT doughnut Natalizumab                 Highly active RRMS               Suboptimal responders ?IFNbeta ...
The relapsing MS DMT doughnut Natalizumab                 Highly active RRMS      Fingolimod               Suboptimal resp...
The relapsing MS DMT doughnut Natalizumab                 Highly active RRMS      Fingolimod               Suboptimal resp...
Emerging concepts in MSNEDD; no evidence of detectable diseaseTTT; treat-to-target
Treat early                                        Natural course                                        of disease       ...
Survival in MS: a randomized cohort study 21years after the start of the pivotal IFN-1b trial                             ...
Establishing long-term efficacy: use of recursive partitioningand propensity score adjustment to estimate outcome in MS   ...
Relationship between early clinical characteristics and long term disabilityoutcomes: 16 year cohort study (follow-up) of ...
100 MSersWho are theresponders?
~20% responders~40% sub-optimal responders~40% non-responders
1      Clinicalvs.            2      MRI            3       NABs
Relapses
Relapse on IFNβ Therapy Increases Risk of         Sustained Disability ProgressionHR of EDSS Increase in Patients with No ...
Relapses and residual deficits                      Lublin FD et al. Neurology. 2003;61:1528-1532.
Predictors of long-term outcome inMSers treated with interferon beta-a                             Bermel et al. Ann Neuol...
Predictors of long-term outcome inMSers treated with interferon beta-1a                             Bermel et al. Ann Neuo...
MRI activity
Predictors of long-term outcome inMSers treated with interferon beta-1a                             Bermel et al. Ann Neuo...
MRI to monitor treatment response to IFNβ: a meta-analysis                                            One New T2 Lesion   ...
MRI to monitor treatment response to IFNβ: a meta-analysis                                              One New Gd+ Lesion...
Disease progression
Strongest predictor of disability progression on                IFNβ therapy is progression itselfDisease activity during ...
Relationship between early clinical characteristics and long term disabilityoutcomes: 16 year cohort study (follow-up) of ...
NABs
Clinical importance of NAbs against IFNβ RRMSers                  Kaplan-Meier Analysis of Time to First Relapse and Propo...
Mean change in EDSS                                                           Kaplan-Meier Estimates of Probability of Sec...
Predictors of long-term clinical response to                           IFNβ therapy in relapsing MS       Variables       ...
Incidence and significance of anti-natalizumab NAbs                                                                  Resul...
Incidence and significance of anti-natalizumab NAbs                          Results from AFFIRM and SENTINEL (cont.)     ...
1      Clinicalvs.            2      MRI            3       NABs
WWW.MS-RES.ORG
WWW.MS-RES.ORG
WWW.MS-RES.ORG
WWW.MS-RES.ORG
Treat-to-targetDisease activity free
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MS Doughnut or Bagel ver. 2

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A talk to a group of colleagues on the 7th Dec 2012 regarding the MS Doughnut!

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MS Doughnut or Bagel ver. 2

  1. 1. Who likes doughnuts? Gavin Giovannoni Barts and The London
  2. 2. Or do you prefer bagels?
  3. 3. Guidelines for the prescribing of IFN-beta and GAFulfil the following 4 criteria: 1. Able to walk independently 2. At least two clinically significant relapses in the last two years Where possible, the patient’s history of relapses should have been confirmed by neurological examination or from another source e.g. hospital or general practitioner’s records, or by discussion with the patient’s main carer. 3. Adult age group (18 years or older) no recommendations are possible in the paediatric age group, since trials have not been performed in this cohort. 4. There are no contraindications Association of British Neurologists Guidelines for the use of Beta Interferons and Glatiramer Acetate in MS, January 2001.
  4. 4. Guidelines for the prescribing of NatalizumabNatalizumab is recommended as an option for thetreatment only of rapidly evolving severe relapsing–remitting multiple sclerosis (RES). RES is defined by two or more disabling relapses in 1 year, and one or more gadolinium-enhancing lesions on brain magnetic resonance imaging (MRI) or a significant increase in T2 lesion load compared with a previous MRI.1st-line or naïve MSers or 2nd-line (IFN-beta or GA failures) NICE - Natalizumab for the treatment of adults with highly active relapsing–remitting multiple sclerosis; August 2007.
  5. 5. Definition of a disabling relapseThere is no accepted definition of a disabling relapse; the following is aworking definition I proposed after Natalizumab got its license:“A disabling relapse is a relapse that causes sufficient neurologicalimpairment to impact on the social and/or occupational wellbeing of theMSer, i.e. to affect their pre-relapse or baseline activities of daily living.In other words from the MSer’s perspective, the disability must be ofsufficient severity to cause a handicap.From a physician’s perspective a disabling relapse would typicallyrequire treatment with corticosteroids and/or admission to hospital.” Giovannoni, Personal communication; August 2007.
  6. 6. Guidelines for the prescribing of FingolimodFingolimod is recommended as an option for the treatment of highly activerelapsing–remitting multiple sclerosis in adults, only if: 1. they have an unchanged or increased relapse rate or on-going severe relapses compared with the previous year despite treatment with beta interferon, and 2. the manufacturer provides fingolimod with the discount agreed as part of the patient access scheme. NICE Fingolimod: final appraisal determination document; 16 March 2012 .
  7. 7. The relapsing MS DMT doughnut
  8. 8. The relapsing MS DMT doughnut Highly active RRMS Suboptimal responders ? Active RRMS Inactive RRMS CIS RIS or asymptomatic MS
  9. 9. The relapsing MS DMT doughnut Natalizumab Highly active RRMS Suboptimal responders ?IFNbeta Active or RRMS GA Inactive RRMS CIS RIS or asymptomatic MS
  10. 10. The relapsing MS DMT doughnut Natalizumab Highly active RRMS Fingolimod Suboptimal responders ?IFNbeta Active or RRMS IFNbeta GA Inactive RRMS CIS RIS or asymptomatic MS
  11. 11. The relapsing MS DMT doughnut Natalizumab Highly active RRMS Fingolimod Suboptimal responders ?IFNbeta Active or RRMS IFNbeta GA Inactive RRMS CIS RIS or asymptomatic MS
  12. 12. Emerging concepts in MSNEDD; no evidence of detectable diseaseTTT; treat-to-target
  13. 13. Treat early Natural course of disease Later treatment Later intervention Treatment at diagnosis Intervention at diagnosis TimeDiseaseOnset
  14. 14. Survival in MS: a randomized cohort study 21years after the start of the pivotal IFN-1b trial Goodin et al. Neurology 2012;78:1315-1322.
  15. 15. Establishing long-term efficacy: use of recursive partitioningand propensity score adjustment to estimate outcome in MS Long-term follow-up 16 years % Risk Relative to Low Exposure IFN-beta exposure 80% vs. 20% Any Negative EDSS=6 SPMS Wheelchair Goodin et al. PLoS One. 2011;6(11):e22444. Epub 2011 Nov 30.
  16. 16. Relationship between early clinical characteristics and long term disabilityoutcomes: 16 year cohort study (follow-up) of the pivotal interferon b-1b trial Goodin et al. J Neurol Neurosurg Psychiatry. 2012 Mar;83(3):282-7.
  17. 17. 100 MSersWho are theresponders?
  18. 18. ~20% responders~40% sub-optimal responders~40% non-responders
  19. 19. 1 Clinicalvs. 2 MRI 3 NABs
  20. 20. Relapses
  21. 21. Relapse on IFNβ Therapy Increases Risk of Sustained Disability ProgressionHR of EDSS Increase in Patients with No Relapses, 1 Relapse, and 2 orMore Relapses During the First 2 Years of IFN Treatment HR SE P Value 95% CINo relapses (reference=1) 1One relapse 3.41 1.47 0.005 1.46–7.98Two or more relapses 4.37 1.74 0.000 1.90–9.57 1.00 No Relapses One Relapse Two or More Relapses Survival Probability 0.75 EDSS Progression 0.50 0.25 HR=hazard ratio; SE=standard error 0 0 20 40 60 80 Analysis Time (Months) Bosca et al. Mult Scler. 2008;14:636-639.
  22. 22. Relapses and residual deficits Lublin FD et al. Neurology. 2003;61:1528-1532.
  23. 23. Predictors of long-term outcome inMSers treated with interferon beta-a Bermel et al. Ann Neuol 2012; In Press.
  24. 24. Predictors of long-term outcome inMSers treated with interferon beta-1a Bermel et al. Ann Neuol 2012; In Press.
  25. 25. MRI activity
  26. 26. Predictors of long-term outcome inMSers treated with interferon beta-1a Bermel et al. Ann Neuol 2012; In Press.
  27. 27. MRI to monitor treatment response to IFNβ: a meta-analysis One New T2 Lesion Odds Ratio Study or Subgroup IV, Random, 95% CI Kinkel 2008 Pozzilli 2005 Prosperini 2009 Sormani 2011Total (95% CI) 2.69 (0.72, 10.04) 0.01 0.1 1 10 100 Disease Less Likely Disease More Likely Two or More New T2 Lesions Odds Ratio Study or Subgroup IV, Random, 95% CI Kinkel 2008 Prosperini 2009Total (95% CI) 9.86 (2.33, 41.70) 0.01 0.1 1 10 100 Favors Experimental Favors Control Dobson et al. Submitted 2012.
  28. 28. MRI to monitor treatment response to IFNβ: a meta-analysis One New Gd+ Lesion Odds Ratio Study or Subgroup IV, Random, 95% CI Kinkel 2008 Pozzilli 2005 Tomassini 2006 Total (95% CI) 3.34 (1.36, 8.22) 0.01 0.1 1 10 100 Disease Less Likely Disease More Likely Two or More New Gd+ Lesions Odds Ratio Study or Subgroup IV, Random, 95% CI Kinkel 2008 Rio 2008 Total (95% CI) 5.46 (2.48, 12.04) 0.01 0.1 1 10 100 Disease Less Likely Disease More Likely Dobson et al. Submitted 2012.
  29. 29. Disease progression
  30. 30. Strongest predictor of disability progression on IFNβ therapy is progression itselfDisease activity during 2 years of treatment and prediction of disability progression* at 6 years Sensitivity (%) Specificity (%)Group (CI) (CI)A. An increase of at least one EDSS step confirmed at 6 months 85 (64–95) 93 (86–97)B. Occurrence of any relapse 80 (58–92) 51 (41–61)C. Occurrence of two or more relapses 45 (26–66) 81 (72–82)D. A decrease in relapse rate less than 30% compared with 2 years 40 (22–61) 86 (77–91) before therapyE. A decrease in relapse rate less than 50% compared with 2 years 40 (–61) 81 (72–88) before therapyF. No decrease or identical relapse rate compared with 2 years 35 (18–57) 88 (79–93) before therapyG. Definition A or B 90 (70–97) 48 (38–58)H. Definition A or E 85 (64–95) 76 (66–83)I. Definition A and B 75 (53–89) 97 (91–99)J. Definition A and E 40 (22–61) 99 (94–99)*EDSS score ≥6.0 or increase in at least 3 EDSS steps. Río J et al. Ann Neurol. 2006;59:344-352.
  31. 31. Relationship between early clinical characteristics and long term disabilityoutcomes: 16 year cohort study (follow-up) of the pivotal interferon b-1b trial Goodin et al. J Neurol Neurosurg Psychiatry. 2012 Mar;83(3):282-7.
  32. 32. NABs
  33. 33. Clinical importance of NAbs against IFNβ RRMSers Kaplan-Meier Analysis of Time to First Relapse and Proportion of Relapse-Free Patients in NAb+ and NAb– Patients* Probability of Remaining Free of Relapse 1.0 0.9 NAb– at 12 months 0.8 NAb+ at 12 months 0.7 0.6 0.5 0.4 0.3 P=0.0369 0.2 0.1 0 0 6 12 18 24 30 36 42 48 54 60 66 Time (months) Number at Risk NAb+ 183 135 95 80 64 45 30 18 11 8 3 NAb– 355 265 216 182 155 112 179 60 41 24 15*Log-rank test; NAb+=NAb positive; NAb–=NAb negative.Sorensen PS et al. Lancet. 2003;362:1184-1191.
  34. 34. Mean change in EDSS Kaplan-Meier Estimates of Probability of Second Relapse During 3-Year Follow-Up in NAb– and Persistent NAb+ Patients* Patients (%) with a Second Relapse 100 NAb– P=0.0064 NAb+ 75 50 25 0 0 6 12 18 24 30 36 Months*Log-rank test.Malluchi S et al. Neurology. 2004;62:2031–2037.
  35. 35. Predictors of long-term clinical response to IFNβ therapy in relapsing MS Variables Odds Ratio 95% CI P Value Baseline T1-hypointense lesion load (cm3) <1.6 1.0 ≥1.6 6.8 (2.3, 20.3) <0.001 At 1-year follow-up Gender Female 1.0 Male 4.9 (1.5, 16.4) 0.009 NAbs Absence (-ve) 1.0 Presence (+ve) 7.3 (2.0, 27.1) 0.003Tomassini V et al. J Neurol. 2006;253:287-293.
  36. 36. Incidence and significance of anti-natalizumab NAbs Results from AFFIRM and SENTINEL 0.5 Placebo with Sustained Disability Progression Cumulative Proportion of Patients NAb– Transiently NAb+ 0.4 Persistently NAb+ 34%*† 0.3 29% (EDSS) 0.2 17% 17% 0.1 0 0 12 24 36 48 60 72 84 96 108 120 Week Number at Risk Placebo 315 296 283 264 248 240 229 216 208 200 NAb– 568 550 538 526 506 487 480 470 460 449 Transiently NAb+ 20 19 18 16 16 16 15 14 14 14 Persistently NAb+ 37 32 26 25 24 22 22 16 16 15*P≤0.05 vs Ab– patients; †P=0.66 vs placebo.Calabresi P et al. Neurology. 2007;69:1391-1403.
  37. 37. Incidence and significance of anti-natalizumab NAbs Results from AFFIRM and SENTINEL (cont.) Incidence of Common Infusion-Related Adverse Events by Antibody Status in AFFIRM and SENTINEL NAb– Transiently NAb+ Persistently NAb+ (n=568) (n=20) (n=37) Natalizumab monotherapy Headache 4 (24)† 0* 19 (7) Urticaria <1 (4)‡ 5 (1) 14 (5) Nausea 1 (8)‡ 0 16 (6) Rigors <1 (1)‡ 0 11 (4) Natalizumab add-on therapy (n=515) (n=32) (n=38) Rigors <1 (1)‡ 0‡ 29 (11) Nausea 1 (7)‡ 0* 18 (7) Headache 4 (20)* 3 (1) 13 (5) Pruritus ≤1 (4)† 3 (1) 11 (4) Flushing ≤1 (3)‡ 0 13 (5) Urticaria ≤1 (2)‡ 0 13 (5) Tachycardia 0‡ 0 11 (4) Dizziness 3 (15) 0 8 (3) Pyrexia <1 (3)† 0 8 (3)Values are n (%).*P<0.05 vs persistently NAb+; †P<0.01 vs persistently NAb+; ‡P<0.001 vs persistently NAb+.Calabresi P et al. Neurology. 2007;69:1391-1403.
  38. 38. 1 Clinicalvs. 2 MRI 3 NABs
  39. 39. WWW.MS-RES.ORG
  40. 40. WWW.MS-RES.ORG
  41. 41. WWW.MS-RES.ORG
  42. 42. WWW.MS-RES.ORG
  43. 43. Treat-to-targetDisease activity free

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