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Patient 1: Deciding When to Initiate Treatment

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  • This slide lists the proposed MRI criteria for determining that clinical events are disseminated in time. The presence of a gadolinium-enhancing lesion is sufficient to indicate dissemination in time if the first positive scan occurs at least 3 months after the onset of the clinical attack. However, the lesion must not be at the site likely responsible for the first event. If, on the other hand, no gadolinium-enhancing lesion is found at this time, a follow-up scan is then required. The group recommends performing the next scan 3 months later. If this scan shows the presence of a new T2-weighted or gadolinium-enhancing lesion, then this fulfills the criteria for dissemination in time. If MRI tests are not performed, the occurrence of a second clinical attack is necessary to fulfill the criteria for dissemination in time. Note: The exact relationship between MRI findings and clinical status of patients is not completely understood. Reference McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: Guidelines from the international panel on the diagnosis of multiple sclerosis. Ann Neurol. 2001;50:121-127.
  • This side provides a visual of the types of MS. Relapsing-remitting (RR) MS is characterized by a pattern of relapses followed by periods of complete remission. It is the most common type, affecting 80% to 85% of patients at onset and 55% of the general MS population at any given time. Secondary-progressive (SP) MS begins as RR, but later disability begins to accumulate independent of relapses. At any given time about 30% of the general MS population is SP. Primary-progressive (PP) MS steadily worsens from the time of onset, with no detectable relapses. PP MS affects about 10% of patients. Progressive-relapsing (PR) MS takes a progressive course upon which relapses are superimposed. PR MS is the least common form, affecting about 5% of patients. Lublin et al. Neurology . 1996;46:907-911.
  • Patients were randomized to either Betaferon or placebo for 24 months; an open-label, 36-month follow-up is in progress. 96% of Betaferon patients opted to continue taking Betaferon by participating in a 3-year extension of the study
  • Only 8 out of 292 patients taking Betaferon who remained adherent to study protocol dropped out from active treatement due to adverse events. “ Majority” is defined as 6 out of 10 patients.
  • As previously discussed, the American Academy of Neurology’s Subcommittee on Therapeutics and Technology Assessment and the MS Council for Clinical Practice Guidelines convened to compose a consensus report on disease-modifying therapies in the treatment of MS. The committee reviewed the pivotal trials of disease-modifying therapies in MS using an evidence-based medicine approach and offered a set of guidelines based on their evidence-based analysis. Reference Goodin DS, Frohman EM, Garmany GP Jr, et al. Disease-modifying therapies in multiple sclerosis: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology . 2002;58:169-178.
  • The INCOMIN (INdependent COMparison of INterferon) study is the first head-to-head comparative trial of 2 disease-modifying therapies for multiple sclerosis (MS). Betaferon ® (interferon beta-1b) and Avonex ® (interferon beta-1a) were compared with respect to clinical and magnetic resonance imaging (MRI) outcome measures. The interim 1-year data analysis was presented at the 53rd annual meeting of the American Academy of Neurology in Philadelphia, Pennsylvania. Durelli et al. Presentation at: Annual Meeting of the American Academy of Neurology; May 2001; Philadelphia, PA.
  • Notes Previous trials have established Rebif as a safe and effective treatment for patients with relapsing-remitting multiple sclerosis (RRMS). The EVIDENCE trial was undertaken to compare the therapeutic effect of two different dosing regimens of interferon beta-1a (IFN β-1a): Rebif 44 mcg tiw SC and Avonex 30 mcg qw IM. 1 Rebif demonstrated clinical superiority over Avonex at 24 weeks in the EVIDENCE head-to-head trial. 1 Based on the results of this trial, Rebif was the first drug to gain exception to the exclusivity granted by the Orphan Drug Act based on superior efficacy in reducing relapse rates. Reference 1. Panitch H, Goodin DS, Francis G, et al, for the EVIDENCE (EVidence of Interferon Dose-response: European North American Comparative Efficacy) Study Group and the University of British Columbia MS/MRI Research Group. Randomized, comparative study of interferon β-1a treatment regimens in MS: the EVIDENCE trial. Neurology . 2002;59:1496-1506.
  • When observing relapse rate, the change between the relapse rates from the final 6-month comparative phase to the noncomparative extension phase was significantly relatively reduced for both the Avonex and Rebif groups (50% and 26% relative reductions, respectively.
  • The INCOMIN (INdependent COMparison of INterferon) study is the first head-to-head comparative trial of 2 disease-modifying therapies for multiple sclerosis (MS). Betaferon ® (interferon beta-1b) and Avonex ® (interferon beta-1a) were compared with respect to clinical and magnetic resonance imaging (MRI) outcome measures. The interim 1-year data analysis was presented at the 53rd annual meeting of the American Academy of Neurology in Philadelphia, Pennsylvania. Durelli et al. Presentation at: Annual Meeting of the American Academy of Neurology; May 2001; Philadelphia, PA.

Transcript

  • 1. MS Patient Cases Iran May 2007 Jack Burks, MD Clinical Professor, Neurologist University of Nevada School of Medicine Reno, Nevada Vice President/Chief Medical Officer Multiple Sclerosis Association of America President Multiple Sclerosis Alliance
  • 2. Important Issues in Treating MS: Illustrative Patient Cases
    • When to start therapy?
    • How to decide on which therapy is the most effective for a specific patient?
    • How should patients be monitored to determine good/poor Rx. responses?
    • What is a poor response to treatment and how should it be managed?
    • How are side effects best managed?
    • What is the future for current and emerging therapies?
  • 3. BG, A 36 year old lady from Sari with severe MS wants a child
    • 36 year old, married11 years, MS started 9 years after Mother died in her arms
    • Initial Symptoms 9 years ago: Fatigue, legs weak, falling.
    • After 3 months Neurologist diagnosed MS by symptoms, exam and MRI with multiple lesions. She does remember an CSF.
    • Treated with IV steroids and improved
  • 4. Sari MS patient
    • Relapse after 4 months, Treated with IV steroids and improved back to “normal”
    • Treated with Betaferon in 2000 and did well until 2004 when she stopped treatment to try “magic” therapy with alternative medicines, herbs and acupuncture.
    • Much worse symptoms until 2004 when saw a Neurologist and got Methetrexate followed by Betaferon. Her MS became more stable.
    • In 2006 stopped Betaferon to become pregnant. She had a miscarriage at 3 months and now wants to become Pregnant again. She fears her may leave her if she doesnot have a child.
    • 3 weeks ago she became paraplegic with decreased feelings in both legs. She is considering Novantrone.
  • 5. 36 year old Sari patient
    • Brief Exam reveals tearful lady with only slight movement in legs in a wheelchair
    • Spasticity in legs with sustained clonus at the ankles
    • Mild to moderate weakness in arms - L. more than R side
    • Ataxia and tremor - L more than R
    • Marked decrease in position sense in legs
    • Cranial nerves OK
  • 6. 36 year old Sari patient
    • Meds include
    • Numerous vitamins
    • Baclofen
    • St John wort
    • Amantadine
    • MRI : 2003 Many T2 lesions
    • : 2005 More lesions with brain atrophy
  • 7. Issues for Sari patient
    • Early Treatment value
    • Problems with Adherence to Betaferon
    • Chemotherapy in lady who wants kids
    • “ Alternative” medicine versus Betaferon
    • Pregnancy desires versus treatment desires
    • Acute treatment and long term treatment options
    • Rehab, Depression and family issues
  • 8. 36 Year old Sari patient: My thoughts on Treatment
    • Must treat relapse immediately with IV steroids!
    • If failure, try plasma phoresis or IVIG.
    • Since she has done well on Betaferon in past, restart with dose escalation ASAP – with IV steroids
    • Treat with Betaferon for one year and re-evaluate. If sub optimal response, try double dose of Betaferon if available data and positive by then. Or consider Novantrone or Tysabri. If she continues to do badly, consider Rituxamab in future – or other new med
    • Rehab, depression Rx and family counseling ASAP
    • Consider adoption and not delay treatment for MS
  • 9. Patient 1: Deciding When to Initiate Treatment
  • 10. Patient 1: Deciding When to Initiate Treatment
    • History
      • 26-year-old secretary, mother of twins; no history of MS or SLE
      • Over 5-day period notices double vision, weakness in the right arm and leg, unsteady gait, fatigue, and difficulty with memory when multitasking
    • Exam
      • Diplopia on right gaze, mild right hemiparesis, and wide-based, slightly ataxic gait
      • Normal bedside mental status
      • Husband stresses patient’s recent disorganization
  • 11. Patient 1: Deciding When to Initiate Treatment
    • MRI
      • 6 periventricular lesions, 1 pontine lesion, 1 high cervical lesion on T2 MRI
      • 4 GAD + lesions
    • Lab work
      • All negative
      • Spinal tap not done
  • 12. Neurologist’s Assessment
    • Patient had a CIS but does not meet the criteria for CDMS, could be ADEM
    • Steroids should be used in this patient, but a DMT is not appropriate at this stage
    • Is this the appropriate diagnosis?
    • What goes into the decision process to determine the appropriateness of utilizing a DMT?
  • 13. Treat Early! Diagnosis of MS in Clinical Isolated Syndrome (CIS) Lesions in Time and Space Clinical Presentation Space Time (Add’l Requirements) (Add’l Requirements) 2 attacks; 2 locations No No 2 attacks; 1 location MRI abnormal or No 2 MRI lesions + CSF 1 attack; 2 locations No MRI  3 months or second attack 1 attack; 1 location (CIS) MRI abnormal or MRI  3 months 2 MRI lesions + CSF or second attack Ref: McDonald, I. Annals of Neurology 2002
  • 14. McDonald MRI Criteria for Dissemination in Time
    • First scan  3 months after clinical event
      • New Gadolinium lesion
        • Must not be the same site
      • No new Gadolinium lesion:
        • Repeat MRI at ≥ 3 months
          • New T2 or gadolinium lesion
    McDonald WI et al. Ann Neurol. 2001;50:121-127. The exact relationship between MRI findings and clinical status of patients is not completely understood.
  • 15. . Example Application of New Diagnostic Criteria  3 months T2 Gd
  • 16. Polman Revision of McDonald Criteria (2005)
    • New T-2 MRI lesions at 1 month after CIS MRI ( lesions in time )
    • Spinal cord lesions can be considered as a brain infratentorial and, if Gd-enhancing, can substitute for a brain Gd-enhancing lesion
    Polman CH et al. Ann Neurol. 2005;58:840-846.
  • 17. Patient 1: Follow-up
    • After being treated with a course of IV Solu-Medrol, the patient’s symptoms improved
    • At a 3-month follow-up visit:
      • Clinical signs resolved
      • Fatigue and memory problems less
      • Neurology exam normal
      • Previous GAD + lesions had resolved
      • 1 new GAD + lesion and 2 new T2 lesions
  • 18. Neurologist’s Assessment at Follow-up
    • Patient meets the McDonald criteria for CDMS/RRMS
    • The patient was started on treatment
    • Do you agree with decision to treat?
    • How do you decide which DMT to utilize in this situation?
    • Is there a difference or are they all the same?
    • What do Evidence Based Medicine Analysis and Class I Head to Head Trial indicate?
  • 19. Patient was treated with IFN β -1b
    • BENEFIT Trial
    • 17 year follow-up data
    • AAN Treatment Guidelines
  • 20. II. BENEFIT: Betaferon in CIS
    • Objective:
      • To assess efficacy, safety, and tolerability of every-other-day (EOD) interferon beta-1b treatment in patients with a clinically isolated syndrome (CIS) suggestive of multiple sclerosis
    • Study design:
      • Randomized, double-blind, placebo-controlled, parallel-group, multicenter study with 468 patients
      • Participants had experienced a first clinical demyelinating event, and at least 2 clinically significant MRI-detected brain lesions
      • Patients received Betaferon 250 µg or placebo SC EOD for 24 months or until CDMS
    • Primary endpoints:
      • Time to CDMS according to the modified Poser criteria
      • Time to diagnosis of MS according to McDonald diagnostic criteria
    Kappos L, Polman CH, Freedman MS, et al, for the BENEFIT Study Group. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology . 2006;67:1242-1249.
  • 21. Design of the BENEFIT study Kappos L, Polman CH, Freedman MS, et al, for the BENEFIT Study Group. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology . 2006;67:1242-1249.
  • 22. Betaferon Reduced the Risk of CDMS by clinical criteria 28% 45% Placebo Betaferon Risk reduction* of 50% over 2 years (Hazard ratio= 0.5) *by adjusted proportional hazards regression days p<0.0001 Clinically Definite MS (%)
  • 23. Betaferon Delayed the Onset of CDMS 28% 45% Placebo Betaferon Clinically Definite MS (%) days 25% + 363 days: + 142% Day 255 Day 618
  • 24. Most Patients Develop MS by MRI Criteria Within 2 Years McDonald MS (%) days Placebo 85% The BENEFIT Study Group MRI MRI MRI MRI MRI MRI MRI 51%
  • 25. Betaferon Doubles the Probability of Not Developing MS
    • Cumulative probability for patients not to develop MS according to McDonald Criteria over 2 years
    Cumulative probability Placebo (n= 176) Betaferon (n= 292) 2 x The BENEFIT Study Group P<0.00001
  • 26. BENEFIT Trial: Early vs. Delayed Treatment: 3 year follow-up (2007)
    • Confirmed Progression (EDSS)
      • Placebo then Betaferon 24%
      • Betaferon from CIS 16%
      • 40% decrease of confirmed progression with early Betaferon treatment! (P=0.02)
    • No effect of NAbs on clinical outcomes
  • 27. BENEFIT study: Discontinuation rates
    • Only 2.7% of Betaferon patients discontinued due to adverse events*
    • The majority of patients experienced no flu-like symptoms over 2 years
    • Factors for low rate of discontinuation include:
    • Dosage Titration
    • Analgesics: before injection
      • *From an analysis of patients who adhere to study protocol.
    The BENEFIT Study. Betaferon ® in newly emerging multiple sclerosis for initial treatment: Clinical results [poster].
  • 28. Lessons from BENEFIT Trial
    • Placebo patients studied in BENEFIT had a high risk of progressing to MS according to the McDonald criteria
      • 85% within 2 years, 51% after 6 months
    • In the BENEFIT study, every-other-day Betaferon significantly
      • Reduced the risk of progression to CDMS (by 50%)
      • Prolonged the time to CDMS by 1 year (+142%) (based on the 25th percentiles)
      • Delayed EDSS disability scores at 3 years
    • Every-other-day Betaferon is well tolerated and well accepted in patients
  • 29. 17 year follow-up Rationale
    • IFNB-1b was approved for the treatment of relapsing forms of multiple sclerosis (MS) based on the results of a double-blind placebo-controlled study in which patients received placebo or IFNB-1b for 104 weeks and were followed up for up to 5 years
    • Results of this pivotal study showed IFNB-1b to be effective and well tolerated over this period
    • There are few data regarding the long-term benefit of IFNB treatment for more than 10 years. However, given that MS evolves over several decades, there is a need for longer-term data on treatment outcomes
    • This study assessed the long-term impact of IFNB-1b therapy in patients involved in the pivotal study
    Ebers, George 2007
  • 30. Credibility factors in Betaferon 17 year follow-up data
    • Positive:
      • Independent analysis
      • Intent to treat analysis: treated vs. placebo
        • About 90% case ascertainment
        • Betaferon effective and safe for 17 years
    • Concerns:
      • Unknown treatment modalities for some patients after trial ended
      • High rate of mortality in placebo group after trial ended. Is untreated MS a potentially fatal disease?
  • 31. Long-term follow-up study: Betaferon significantly delayed disease progression over 17 years of treatment
    • Patients who continuously used Betaferon had nearly 60% more cane-free years from time of diagnosis*
    • Treatment with Betaferon delayed progression to SPMS by 6.6 years compared to other treatments or no treatment
    • After 17 years, the tolerability and safety profile of Betaferon remains excellent
    *Versus patients on other DMTs or no treatment. Goodin DS, Ebers G, Traboulsee A, et al, for the Betaferon ® LTF Study group [poster]. American Neurological Association. October 8-11, 2006. Ebers G, Traboulsee A, Langdon D, Goodin D, Konieczny A, for the Betaferon ® /Betaferon ® LTF Study Group [poster]. American Academy of Neurology. April 1-8, 2006.
  • 32. Betaferon 17-Year LTF: Mortality Data by treatment group
    • Betaferon standard dose (n=124) 6%
    • Betaferon lower dose (n=125) 9%
    • Placebo (n=123) 19%
  • 33. Using Evidenced Based Medicine to Guide MS Therapy
    • AAN Guidelines
    • Cochrane Committee Reports
    • Head to Head Class I Trials
  • 34. Evidence-based Medicine: AAN Guidelines Goodin DS, et al. Neurology . 2002;58:169-178.
  • 35. AAN Guidelines on DMT’s
    • Relapses and MRI
      • All better than placebo (A)
    • Disability Progression
      • Interferons: Probably Effective (B)
      • Copaxone: Possibly Effective (C)
    • IFNs: Higher Dose / frequency more effective (B)
    • NAb: Conflicting data (U)
      • Utility of measuring is uncertain
      • Did not recommend testing requirements
  • 36. Patient 2: Evaluating the Response to Disease Modifying Therapy (DMT) in MS
  • 37. Patient 2: Evaluating Response to DMT
    • Current complaint
      • 28-year-old surgical resident with RRMS
      • Recently developed fatigue and frustration but without impairment of surgical skills, even during extended operations
      • She is considering changing her MS therapy
  • 38. Patient 2: Evaluating Response to DMT (Cont.)
    • Past Neurological History
      • 3.5 yrs ago: first symptom (unsteadiness of gait) resolved without treatment or evaluation
      • 3 years ago: bladder urgency, difficulty handwriting, mild weakness in right leg
        • Brain MRI revealed 2 GAD+ lesions and 10 T2 lesions: locations included periventricular areas, brain stem, cerebellum and corpus Callosum.
        • CSF: + bands and IgG Synthesis: Other labs normal
        • Diagnosis of RRMS was made and treatment was I.V. Steroids for 5 days. IFN B-1b was also begun. She recovered completely in one month
      • 6 months later: mild blurred vision in left eye for two weeks with spontaneous recovery without steroids. No Evaluation
  • 39. Patient 2: Evaluating Response to DMT (Cont.)
    • Current evaluation:
      • Neuro Exam Normal: Possible depression?
      • MRI: No GAD lesions: T2 lesions are smaller. No black holes or atrophy
      • NAb test: + (1:100 titer)
  • 40. Neurologists Assessment
    • Since IFN B-1b, this patient has had only one episode of (likely) mild optic neuritis – shortly after beginning therapy 3 yrs ago
    • Neuro exam was normal
    • MRI demonstrated improvement since beginning therapy
    • Patient does not have enough evidence to diagnose “suboptimal response” to current therapy.
  • 41. Neurologist’s Action Plan
    • Patient should remain on IFN B-1b
    • Treat symptomatically for fatigue & depression
    • Patient and NAb status should be reevaluated in 6 months
  • 42. Questions
    • What is the utility of NAb testing in this clinically stable patient?
    • What will be the patient’s response to changing a treatment that is apparently working, especially if the change results in a treatment that may not work as well?
  • 43. Comments
    • There remain differences of opinion regarding the use NAb testing. 2007 AAN guidelines using EBM principles do not support routine NAb testing because
      • No class I EBM results on utility of NAb testing
      • No standardized NAb test
      • No established level of NAb relevance (?100-200) titer
      • No EBM data on timing of NAb test
      • No EBM data on clinical outcomes after changing therapy based on + NAb test
    • Recent data fails to correlate NAbs with poor response to treatment.
  • 44. Neutralizing Antibodies to Interferon B-1b are not Associated with Disease Worsening in Multiple Sclerosis
    • Goodin DS., Hurwitz B., Noronha A. The Journal of International Medical Research , 2007; 35: 173-187
  • 45. NAb Results: 6698 Patients
    • Australia: All Patients on IFN β -1b
      • 37% NAb positive
    • North America: Suboptimal Responders
      • 21.3 % NAb positive
    • Europe: Suboptimal Responders
      • 27.6% NAb positive
    Goodin, 2007
  • 46. Conclusions:
    • Poor responders were less likely to have NAbs than responders
    • NAbs are not responsible for poor clinical responses and that NAb status is of little clinical value .
    Goodin DS., Hurwitz B., Noronha A. The Journal of International Medical Research , 2007; 35: 173-187
  • 47. Evaluating Response to DMT: Patient 2 Follow-up
    • 6 months later she was NAb Θ on retest
    • The patient has remained on IFN B-1b with no new symptoms for the last 2 years
    • Modafinil was added for fatigue: improvement
    • SSRI taken for depression for one year.
    • She is now a fully functioning surgeon with no depression and minimal fatigue
  • 48. Patient 4: Managing Side Effects of DMT's
  • 49. Patient 4: Managing Side Effects of DMT’s
    • 34 yr old RRMS patient has been on IFN B-1b for 4 months
    • Neurologically stable but experiences flu like side effects and redness/pain at injection sites. She is unable to work because she feels “sick”, agitated, and depressed. Although feeling better in the past 2 months, she still wants to stop or switch treatment.
    • Initially she was started on the full dose of IFN B-1b without titration or analgesia pre-injection medication. Her husband has been injecting the drugs at an angle “to avoid going too deep”.
    • Liver function and CBC tests are normal
    • MRI is unchanged
  • 50. Neurologist’s Assessment
    • Since beginning therapy she has had no relapses or new MRI lesions
    • Side effects are caused by lack of dose titration when starting treatment and improper injection technique (Intradermal injections).
    • Depression could be from learning of her diagnosis of MS or worry about drug side effects vs. a direct effect from drug.
  • 51. Neurologist’s Actions
    • Drug holiday for one month
    • Re-start IFN B-1b at ¼ dose and titrate to ½, then ¾ and then full dose each 2-3 weeks
    • Close supervision and counseling
    • Take analgesics before each shot
    • Inject at 90 degrees
    • Evaluate for depression on each visit, but no anti depression medication at this time
  • 52. Patient 4: Outcome
    • At 1 year patient tolerated treatment well with very few side effects and no recurrence of depression symptoms.
    • No missed days from work
  • 53. Patient : Discussion
    • Drug side effects may mimic worsening of MS
    • Proper initiation of therapy prevents most early side effects
    • Aggressive side effect management can often avoid terminating therapy
  • 54. Patient 5: Evaluating Possible Treatment Failures
  • 55. Patient 5: Deciding When Treatment Is Not Working
    • A 43-year-old patient seeks a second opinion
    • 5-year history MS
    • Treated for 3 years with IFNβ-1a IM weekly
    • Clinical exam
      • Weakness in extremities (worst in left lower)
      • Uses cane for balance (4 months)
      • Bilateral extensor plantar responses
      • decreased vibration and position sensation in both legs and left hand
      • Dysmetria bilaterally on finger to nose, and rapid alternating movements bilaterally; dysmetria on heel to shin
      • Mild memory dysfunction
  • 56. Patient 5: Summary of Disease Course
    • A 43 yr old salesman is referred to you for a second opinion
    • Case history
    Negative Negative Negative ND ND NAb status Yes Yes Yes No No IFNβ-1a IM Yes No No No No Progression Yes No No No No Cognitive dysfunction Yes Yes No No No Brain atrophy 1 2 1 2 4 GAD + lesions  ↑ ↑ ↑ 12 T2 lesions 1 2 1 1 1 Exacerbations 2006 2005 2004 2003 2002  
  • 57. Neurologist’s Assessment
    • The initial diagnosis of RRMS was correct
    • The patient had 4 exacerbations during the 3 years on INF B-1a IM weekly
    • The disease has transitioned from RRMS to SPMS in the past 6 months
    • Response to IFNB-1a has been suboptimal in spite of negative NAb testing
    • Therefore, treatment was switched to IFN B-1b, 250 mcg god
  • 58. Questions Raised by Patient 5
    • Was DMT started at the right time?
    • What did his NAb test results mean?
    • When did this patient’s disease become sub-responsive to IFN B-1a IM?
    • What criteria are most important for determining when a patient has a suboptimal response to treatment?
    • When should natalizumab, and/or immunosuppressant drugs be considered?
  • 59. Patient 5: Summary of Disease Course
    • A 43 yr old salesman is referred to you for a second opinion
    • Case history
    Negative Negative Negative ND ND NAb status Yes Yes Yes No No IFNβ-1a IM Yes No No No No Progression Yes No No No No Cognitive dysfunction Yes Yes No No No Brain atrophy 1 2 1 2 4 GAD + lesions  ↑ ↑ ↑ 12 T2 lesions 1 2 1 1 1 Exacerbations 2006 2005 2004 2003 2002  
  • 60. Deciding When Treatment Is Not Working: Discussion
    • To provide optimal, care one must be prepared to change treatment if the course of the disease changes
    • Worsening neurological status (including cognition) with or without relapses are the most important criteria for deciding if a patient is progressing
  • 61. Differential Diagnosis for Worsening Symptoms on DMT's
    • Poor compliance (common)
    • Side effects of DMT’s
    • Co-morbid conditions (hypothyroid, anemia, depression, infection)
    • Suboptimal Response (SORs) to DMT
      • Diagnosis challenging (vs. natural treatment history)
      • Under-diagnosed: (30%)
      • Treatment unclear: Lack of EBM data
  • 62. Identifying SORs: Ongoing documentation is critical
    • Relapses
    • Progression of Disability
    • New MRI lesions (GAD lesions on T1)
    • Increased MRI Burden of Disease (T2)
    • Cognition? Often overlooked /undocumented
    • New Imaging technologies? Not Yet
  • 63. SOR: When to think about changing treatment?
    • Major relapse
    • 2 minor relapses in one year (Documented)
    • EDSS progression - not related to relapse
    • Decrease in cognitive function on testing
    • 1 new GAD lesion on MRI (Interferons)
    • 2 new T-2 lesions in MRI in one year
    • NAbs?
  • 64. SOR: When to think “Why should I NOT Change treatment?”
    • 2 major relapses in one year
    • Documented further EDSS progression on 2 exams 6 months apart
    • Documented further decline of cognition on 2 exams 6 months apart.
    • 2 or more GAD lesions in 2 years (interferons)
    • 3 or more new T-2 lesion in 2 years
    • Considerable increase in brain atrophy, permanent black holes
  • 65. Management of SOR
    • Data is incomplete: Little EBM data:
    • “ Therapeutic Window” is closing
    • Increase dose/frequency within class of drug
    • Change class of treatment
    • Add drug/combination therapy
  • 66. Managing SOR on Avonex
    • Increase Dose
      • Double Dose weekly: Negative results
    • Increase frequency
      • Give every 2-4 days, IM: No data: ?Practical
    • Switch to higher dosed, more frequent Interferon
      • Betaferon: INCOMIN Trial Data (MRI-Class I)
      • Rebif: EVIDENCE Trial Data (Class I)
          • : EVIDENCE Trial Extension Data: Not Class I
    • Switch to or add Copaxone: No Data: Combination Trial underway: Appears safe
    • Add/switch to Mitoxantrone or other immuno-suppressants
    • Switch to Natalizumab
  • 67. INdependent COMparison of INterferon (INCOMIN) Trial Study Group Durelli et al. Lancet 2002, 359:1453-60 A Multicenter Trial Comparing Clinical and MRI Efficacy of Betaferon ® and Avonex® in RRMS
  • 68. Betaferon vs. Avonex The INCOMIN Trial Results: First 24 Months NAbs did not effect outcomes Avonex Betaferon (n=92) (n=96) %  p T2 Lesion Free (0-24 mo) 19 (26%) 42 (55%) +53% 0.0003 % Change Lesion Load +11.7% -2.8% >100 0.0001 EDSS progression (0-24 mo) 28 (30%) 13 (14%) -46 0.005 New T2 lesions (6-12 mo) 33 (45%) 16 (21%) -52 0.002 Gd+ lesions (6-12 mo) 16 (22%) 7 (9%) -56 0.03 Gd Lesion Free (0-24 mo) 18 (25%) 39 (51%) +51 0.0008 Relapse-free (0-24 mo) 30 (33%) 46 (48%) +35 0.036
  • 69. The EVIDENCE Trial
    • Head-to-head, randomized, open label, evaluator-blinded comparison of Rebif (44 mcg tiw SC) with Avonex (30 mcg qw IM) in patients with RRMS
    • Neurology. 2002;59:1496-1506
    EV idence of I nterferon D ose-response: E uropean N orth American C omparative E fficacy Trial Panitch H. Neurology 59: 1496-1503 (2004)
  • 70. Summary Efficacy at Week 24 and Week 48 Week 24 Week 48 p - value Relative improvement p - value Relative improvement Odds ratio - relapsing 0.0005 47% 0.009 33% Hazard ratio, time to relapse 0.001 37% 0.003 30% Relapse rate 0.025 26% 0.093 16% CU active <0.001 48 % T2 lesions <0.001 50% <0.001 36% T2 active scans <0.001 45% <0.001 38% T2 inactive patients <0.001 39% <0.001 40% Rebif vs Avonex Rebif vs Avonex Panitch H. Neurology 59: 1496-1503 (2004)
  • 71. Avonex to Rebif Switch Trial Annualized Relapse Rate Final Comparative Phase vs Posttransition Phase Panitch H. Neurology 59: 1496-1503 (2004) Rebif 44 mcg tiw f inal comparative phase Avonex 30 mcg qw final comparative phase Rebif 44 mcg tiw posttransition from Rebif/Avonex 26% 0 0.2 0.4 0.6 0.8 Annualized relapse rate (mean) Avonex to Rebif (n=223) P < 0.001 P = 0.028 50% Rebif to Rebif (n=272) 0.46 0.34 0.64 0.32
  • 72. Managing SOR on Avonex
    • Increase Dose
      • Double Dose weekly: Negative results
    • Increase frequency
      • Give every 2-4 days, IM: No data: ?Practical
    • Switch to higher dosed, more frequent Interferon
      • Betaferon: INCOMIN Trial Data
      • Rebif: EVIDENCE Trial Data
          • : EVINDENCE Trial Extension Data
    • Switch to Copaxone: No EBM data: Safe
    • Add Copaxone: No Data: Combination Trial underway: Appears safe
    • Add/switch to Mitoxantrone or others
    • Switch to Natalizumab
  • 73. Managing SOR on Betaferon
    • Increase Dose: Reasonable Pilot data: Well tolerated
      • OPTIMS Trial
      • BEYOND Trial
    • Switch to Rebif: No data:
    • Switch to Avonex:
    • No: INCOMIN Dose Reduction study
    • Switch to Copaxone: Safe, No EBM data
    • Add Copaxone: No data
    • Add/Switch to Mitoxantrone or other immunosuppression
    • Switch to Natalizumab
  • 74. INdependent COMparison of INterferon (INCOMIN) Trial Study Group Durelli et al. Lancet 2002, 359:1453-60 A Multicenter Trial Comparing Clinical and MRI Efficacy of Betaferon ® and Avonex® in RRMS
  • 75. Dose-Reduction Study Betaferon ® to Avonex ® Switch Trial Avonex ® Betaferon ® Exacerbation rate .09* .02* % of patients with exacerbations 77%* 21%* % of patients with sustained 23% (ns) 0% (ns) EDSS worsening % of patients with MRI activity 85%* 36%* * Statistically significant p <0.05 INCOMIN Trial Continuation Barbero P. J. Neurol Sci. 15;222(1-2):13-9 (2004)
  • 76. Managing SOR on Betaferon
    • Increase Dose: Reasonable Pilot data: Well tolerated
      • OPTIMS Trial
      • BEYOND Trial
    • Switch to Rebif: No data
    • Switch to Avonex: No: INCOMIN Dose Reduction study
    • Switch to Copaxone: Safe, No EBM data
    • Add Copaxone: No data
    • Add/Switch to Mitoxantrone or other immunosuppression
    • Switch to Natalizumab
  • 77. Managing SOR on Rebif
    • Increase Dose: No data: Not very practical
    • Switch to Betaferon: No data: Maybe easier to give even higher dose
    • Switch to or add Copaxone : No data. Safe
    • Add/Switch to Mitoxantrone or other immunosuppression
    • Switch to Natalizumab
  • 78. Managing SOR on Copaxone
    • Increase dose? Double dose: positive PILOT data
    • Switch to Interferon: No EBM data: Most popular option: safe
    • Add Interferon: Combination Trial underway: safe
    • Add/switch to Mitoxantrone or others
  • 79. Other SORs Treatment Options Immunosuppression:
    • Mitoxantrone (Novantrone)
      • For worsening MS (RRMS and SPMS)
      • Approved by FDA
      • Popular for SOR treatment of ABCR drugs
      • Relatively well tolerated
      • Issues:
        • Occasional permanent amenorrhea
        • Cardiotoxicity: Dose dependent (2-3) years
        • Uncommon Risk of Leukemia (1 in 500?)
  • 80. Other SOR Options
    • Pulses Methylprednisolone (I.V., monthly)
    • Methotrexate (oral, weekly)
    • Azathioprine (Imuran) (oral, daily)
    • Cyclophosphamide (Cytoxan)
    • Micophenolate (Cell Cept)
    • IVIG
    • Tysabri (Natalizumab): DO NOT ADD!
    • Natalizumab (Tysabri) switch
  • 81. Summary & Conclusions: SOR Diagnosis
    • SORs are common (30% or greater) but are under diagnosed
    • Is patient Compliant with drug?
    • Regular documentation of MS course is crucial: Relapses, MRI lesions, disability progression, ? Cognition
    • Rule out other causes of worsening MS : co-morbid conditions, pseudo exacerbations, depression, UTI, thyroid dysfunction
  • 82. Summary & Conclusions: SOR Treatment
    • Little EBM data but therapeutic window closing: Options include:
      • Increase dose/frequency within class
      • Change class of treatment
      • Add different class of therapy (not natalizumab)
  • 83.
    • What is New?
    • Current and Emerging Therapies
  • 84. A. Betaferon
      • BENEFIT Trial in CIS
      • 17 Year Follow up data
      • Betaferon vs. Double Dose Betaferon vs. Copaxone
  • 85. B. Rebif
      • Reformulated Rebif
      • Rebif vs. Copaxone
      • Rebif in CIS
      • Cladribine Induction before Rebif
      • Rebif vs. Betaferon tolerability study
  • 86. C. Copaxone
    • Copaxone in Primary Progressive MS: Discouraging
    • Double Dose Copaxone in RRMS: Encouraging
    • Copaxone in CIS (in progress)
    • Copaxone vs. Betaferon (in progress)
    • Copaxone vs. Rebif (data being analyzed)
  • 87. D. Natalizumab (Tysabri)
      • Natalizumab vs. Placebo in RRMS
      • Natalizumab vs. Avonex
      • The PML issue
  • 88. Oral Therapies
    • May improve convenience and compliance in MS therapy
    • Oral therapies now in phase 3 trials may be available in late 2010
      • Fingolimod (FTY720)
      • Teriflunomide
      • Cladribine
      • Laquinimod
  • 89. Monoclonal Antibodies (MAbs): Background
    • MAbs offer more favorable dosing regimens compared with current MS therapies (less frequent)
    • MAbs currently in use appear to be associated with specific side effects, eg, PML, Graves disease, ITP
    • Clinical trials of MAbs in MS are less advanced than those of oral therapies
    • Possible that no MAb currently in development will enter MS market before 2010
  • 90. MAbs: Conclusions
    • Some striking efficacy results with MAbs in MS
    • Safety concerns must be allayed before MAbs are widely used in MS
  • 91. Other Emerging Treatments
    • Fingolimod (oral)
    • Campath (yearly)
    • MBP82-98 (6 months)
    • Rituximab (B-cell AB) (? PML)
    • Cladribine (oral)
    • Fumarate (BG-12) (oral)
    • Teriflunomide (oral)
    • Statins (oral): blocks IFNs
    • Minocycline (oral
    • Estriol (oral)
    • Laguinimod (oral)
    • Fampridine-SR (Ambulation)
    • NeuroVax (T-cell vaccine)
    • Tovarin (anti T-cell)
    • Bone Marrow Transplant
    • IVIG
    • Stem Cell Transplant
    • Marijuana (symptomatic)
    • Testosterone (Cognitive)
    • Small Molecules
    • CellCept (mycophenolate)
  • 92. Other Treatment Approaches
    • Stem cells (bone marrow and embryonic)
    • Remyelinating agents
    • Neuroprotective agents
  • 93. Patient 5A: Management of Suboptimal Responders to both low and high Dose Interferons
  • 94. Patient 5A
    • 39 year old male with very active RRMS for 3 years. He averages 2 attacks per year for all three years with only partial response to IV steroids. He was started on INF β 1-a I.M. (Avonex) weekly for the next two years. He was then switched to Rebif 44 TIW for the past year. He had 2 attacks during that last year with incomplete recovery with steroids.
  • 95. Patient 5A
    • He is stable between attacks, but ongoing MRI activity is present. His exam reveals a bilateral intramuscular opthalmoplegia; right hemiparesis and ataxic gait requiring a cane to walk (EDSS=6).
  • 96. Patient 5A
    • What is your best treatment option
      • Keep on Rebif but double the dose
      • Get an NAb test and stop Rebif if positive
      • Switch to IFN β -1b at double dose (500 ug)
      • Add or Switch to Mitoxantrone
      • Add or switch to Azathioprine
      • Add or switch to cyclophosphide
      • IVIG
      • Add Natalizumab (No!)
      • Switch to Natalizumab
      • Other options?
  • 97. Patient 5B A 36 year old lady from Sari with severe MS wants a child
    • 36 year old, married11 years, MS started 9 years after Mother died in her arms
    • Initial Symptoms 9 years ago: Fatigue, legs weak, falling.
    • After 3 months Neurologist diagnosed MS by symptoms, exam and MRI with multiple lesions. She does remember an CSF.
    • Treated with IV steroids and improved
  • 98. Sari MS patient
    • Relapse after 4 months, Treated with IV steroids and improved back to “normal”
    • Treated with Betaferon in 2000 and did well until 2004 when she stopped treatment to try “magic” therapy with alternative medicines, herbs and acupuncture.
    • Much worse symptoms until 2004 when saw a Neurologist and got Methetrexate followed by Betaferon. Her MS became more stable.
    • In 2006 stopped Betaferon to become pregnant. She had a miscarriage at 3 months and now wants to become Pregnant again. She fears her may leave her if she doesnot have a child.
    • 3 weeks ago she became paraplegic with decreased feelings in both legs. She is considering Novantrone.
  • 99. 36 year old Sari patient
    • Brief Exam reveals tearful lady with only slight movement in legs in a wheelchair
    • Spasticity in legs with sustained clonus at the ankles
    • Mild to moderate weakness in arms - L. more than R side
    • Ataxia and tremor - L more than R
    • Marked decrease in position sense in legs
    • Cranial nerves OK
  • 100. 36 year old Sari patient
    • Meds include
    • Numerous vitamins
    • Baclofen
    • St John wort
    • Amantadine
    • MRI : 2003 Many T2 lesions
    • : 2005 More lesions with brain atrophy
  • 101. Issues for Sari patient
    • Early Treatment value
    • Problems with Adherence to Betaferon
    • Chemotherapy in lady who wants kids
    • “ Alternative” medicine versus Betaferon
    • Pregnancy desires versus treatment desires
    • Acute treatment and long term treatment options
    • Rehab, Depression and family issues
  • 102. 36 Year old Sari patient: My thoughts on Treatment
    • Must treat relapse immediately with IV steroids!
    • If failure, try plasma phoresis or IVIG.
    • Since she has done well on Betaferon in past, restart with dose escalation ASAP – with IV steroids
    • Treat with Betaferon for one year and re-evaluate. If sub optimal response, try double dose of Betaferon if available data and positive by then. Or consider Novantrone or Tysabri. If she continues to do badly, consider Rituxamab in future – or other new med
    • Rehab, depression Rx and family counseling ASAP
    • Consider adoption and not delay treatment for MS
  • 103. Patient 6: The Dilemma of “Asymptomatic” MS
  • 104. Patient 6
    • 24 year old female with bitemporal throbbing “migraine” headaches associated with nausea, vomiting for 4 years associated with menstrual periods. Headaches last 2-6 hours and are helped with sumatriptan (Imitrex) if taken early in the course of the headache. She denies any fevers or chills. She is otherwise healthy with no family history of Neurological disease. No history of previous head injury.
  • 105. Patient 6
    • Her neurological exam was normal. MRI was done to rule out Meningioma, Aneurysm, or Arterial-venous malformation (AVM). Her T-2 weighted MRI revealed 6 white matter lesions ranging from 3-8mm, mainly periventricular. Radiologist conclusion “Multiple lesions, consistent with multiple sclerosis”.
  • 106. Patient 6
    • She comes to you for a second opinion:
    • Does she have MS? (or something else?)
    • Should she have an L.P., another MRI (GAD?), Evoked Potential testing, other workups?
    • Should she be treated with steroids or specific MS therapies
  • 107. Patient 6
    • What is your Differential Diagnosis?
    • How would you work up and treat this patient?
  • 108. Patient 6 Differential Diagnosis
    • Collagen vascular disease (SLE)
    • CADASIL
    • Thyroid disease
    • Hypoglycemia
    • Vitamin deficiencies
    • Sj ö gren syndrome
    • Beh ç et’s disease
    • Myasthenia gravis
    • Spino-cerebellar
    • Degeneration
    • Adrenoleukodystrophies
    • Lyme disease
    • Syphilis
    • TB & other CNS infections
    • Sarcoidosis
    • CNS malignancy
    • CNS embolic disease
    • AIDS
    • PML
  • 109. Patient 6 Evaluation for MS: Diagnosis and Progression
    • Clinical history and exam best
    • Ancillary tests
      • MRI
      • CSF
      • Evoked potentials
      • Urological testing
      • Cognitive tests
      • EDSS, MSFC scale, Scripps scale
  • 110. Patient 6
    • Her evoked potential tests, ANA, Sed Rate, thyroid screen, VDRL, and other screening tests are normal. She has no GAD lesions or new T-2 lesions on repeat MRI done 2 weeks later. CSF is normal
  • 111. Patient 6
    • Would you diagnose MS?
    • Would you treat with Steroids?
    • Would you treat with Interferons?
    • Would you treat with both Steroids & Interferons?
  • 112. Patient 6
    • She was not given the diagnosis of MS and was not treated
  • 113. Patient 6
    • If she had an identical twin with MS, would that change your opinion?
      • Identical twins have a 30% concordance rate for MS
  • 114. Patient 6
    • One year later, she remained asymptomatic with a normal exam, but a repeat MRI showed 2 new T-2 lesions, but no GAD + lesions.
    • Does she now have MS?
    • Would you treat?
  • 115. Patient 6
    • She was not diagnosed as MS and was not treated
  • 116. Patient 6
    • One year later she had an episode of numbness on left arm and leg along with fatigue and ataxia. Her MRI revealed 4 new T-2 lesions and 2 GAD + lesions
    • Would you diagnose MS?
    • Would you treat with Steroids?
    • Would you treat with Interferons?
    • Would you treat with both Steroids & Interferons?
  • 117. Patient 6
    • She was diagnosed as MS and treated with steroids and Interferon β -1b with no further attacks in 5 years of follow-up.
    • Her MRI revealed no new T-2 or GAD lesions.
    • Would you stop her Interferon Treatment?
  • 118. Patient 7: Differentiating MS, Neuromyelitis Optica (DEVIC’s), and Asian Optica-spinal MS
  • 119. Patient 7
    • 18 year old Asian male presented with decreased vision in right eye over 3 days with pain on eye movement: ophthalmologist diagnosed “optic neuritis” and treated with IV steroids with good results. Four months later he developed numbness and weakness in his legs with difficulty walking over a one week time period. His examination showed optic palor on right, decreased sensation below umbilicus and decreased strength in both legs.
  • 120. Patient 7
    • Babinski test was positive bilaterally, DTR’s were very active with transient clonus at At ankles. CSF tests were negative, except for 15 WBCs, MRI of spine showed a patchy longitudinal lesion from L1-4. Brain MRI showed 2 periventricular T-2 lesions. Extensive work up for other diseases was negative but acquaporin-4 antibody test was positive.
  • 121. Patient 7
    • What is the most likely diagnosis?
      • Classical MS
      • Asian MS (optic-spinal MS)
      • Neuro myelitis optica (NMO or Devics Disease)
      • CNS lymphoma or metastatic cancer
      • Other
  • 122. Neuromyelitis Optica Optic-Spinal MS Recurrent Optic Neuritis Recurrent Myelitis
  • 123. Spectrum of MS: Neuromyelitis Optica (DEVIC's)
    • NMO
      • Gender predilection: Female to Male ~10:1
      • Onset in all ages
      • Ethnic predilection: No clear ethnic predilection
        • May be present in all areas of the world at very low prevalence
        • In areas with high prevalence of MS, may be misdiagnosed as atypical MS
        • In areas with low MS prevalence, differentiation from classic MS becomes easier
    • Investigation
      • Spinal cord–longitudinally extensive, central necrotic lesions
      • Brain–some lesions now permitted
      • CSF–pleocytosis (>50 white cells/μL), polymorphonuclear cells, oligoclonal band negative
      • NMO Antibody (Aquaporin 4) found in 70%
  • 124. Spectrum of MS: Optic-Spinal Multiple Sclerosis
    • OSMS (Asia)
      • Gender predilection: Female to Male ~3:1 or more
      • Ethnic predilection: Far-east Asian, Japanese, Latin American
    • Investigation
      • Brain–generally normal, but typical MS-like lesions can be observed
      • Spinal cord–multiple cord lesions of variable lengths
      • CSF–Oligoclonal bands in about 30% of cases
      • NMO Antibody found in >50% if long cord lesions (?NMO)
  • 125. Spectrum of MS Recurrent Optic Neuritis
    • If Brain and Spinal cord MRI normal
      • CDMS less likely
      • BUT may convert to CDMS years later
      • Treat with IV steroids, not DMT's
  • 126. Spectrum of MS Recurrent Myelitis
    • If brain MRI normal, unlikely CDMS
    • If NMO Antibodies +, may be NMO
    • Treat with IV Steroids and Immunosuppressants
  • 127. Patient 7
    • Patient was diagnosed as DEVIC’S (NMO)
    • He was treated with IV steroids only. He recovered considerable function but not completely.
  • 128. Patient 7
    • Eight months later has another episode with decreased vision in left eye and numbness from his mid chest to his legs. Thoracic MRI revealed a new thoracic lesion covering 3 segments
  • 129. Patient 7
    • How would you treat him?
      • No treatment
      • IV Steroids
      • Interferon
      • Azathioprine
      • Mitoxantrone
      • Rituximab
      • Cyclophosphamide
      • IVIG
      • Natalizumab
      • Other drugs
  • 130. Patient 7
    • He was treated with IVMP and Aziathiaprine. He had 2 more attacks within the next 18 months, which left him blind in his left eye and he required a cane to walk. He was switched to IVIG and had another attack in 3 months. He was switched to Rituximab and has had no further attacks in 1 year of follow up