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Treatment Choices in MS

Treatment Choices in MS. Treatment of MS. Aspects of treatment are focused on: Early intervention Symptomatic treatment Treating Acute relapse Disease modification and immunosupression Despite major advances for many patients, symptomatic treatment continues to be the mainstay of care.

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Treatment Choices in MS

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  1. Treatment Choices in MS

  2. Treatment of MS • Aspects of treatment are focused on: • Early intervention • Symptomatic treatment Treating • Acute relapse • Disease modification and immunosupression • Despite major advances for many patients, symptomatic treatment continues to be the mainstay of care

  3. Treatment goals • Early intervention • Treat relapses • Reduce the likelihood of future relapses • Relieve individual symptoms • Provide rehabilitation for persistent problems • Optimising functional ability • Delay disease progression • Prevent secondary complications • Maximise quality of life

  4. Management strategy Treatment must address • Inflammation, neuro-degeneration and neuro protection • Chronic nature of disease process • Sub-acute/acute exacerbations • The individual’s unique presentation

  5. Optimal management Treatment of acute relapses • anti-inflammatory Disease modifying treatment (DMT) • Suppress destructive immune response • Neuroprotection? Symptomatic treatment • Remains essential Holistic assessment Multidisciplinary input • Rehabilitation for persistent problems • Maintenance of capabilities despite changing abilities • Complementary therapies Promote self management

  6. Treating symptoms

  7. Treating symptoms • Aim to maximise quality of life • Required by most patients at some time • Addresses: • Short-term changes & relapse symptoms • Long-term: limiting disabilities and secondary complications • Symptom diary helps in management • Aims to minimise the impact of symptom interaction

  8. Managing Relapses

  9. Treatment of relapses • Assessment • Take history • Confirm relapse • Determine severity, functional disability / loss • Exclude infection • Medication • Supportive therapy • Physiotherapy; occupational therapy; counselling • Care package • Hospital admission for severe relapse

  10. Relapse management NICE Recommendations: • Any individual who experiences an acute episode sufficient to cause distressing symptoms or an increased limitation on activities should be offered a course of high-dose corticosteroids • intravenous methylprednisolone 500mg – 1g for 3 to 5 days • high-dose methylprednisolone 500mg – 2g daily for 3 to 5 days • An individual should be given a clear explanation of the risks and benefits involved in taking corticosteroids • Prolonged and frequent courses should not be used NICE MS Guidelines. 2004 National Clinical Guideline for Diagnosis and Management in Primary and Secondary Care

  11. Steroids for relapses • Anti-inflammatory effect • Suppress immune system • Stabilise blood brain barrier • Thought to speed recovery • BUT do not influence degree of recovery or long-term progression of disease • Side effects minor but include weight gain, acne, cataracts, osteoporosis and diabetes • The NICE Guideline recommends courses of steroids be limited to a maximum of three times a year NICE MS Guidelines. 2004 National Clinical Guideline for Diagnosis and Management in Primary and Secondary Care

  12. Disease Modification

  13. Disease modification Therapeutic considerations • Long-term efficacy of treatments • Benefits vs risks • Side effect profiles • Co morbidity • Concomitant medication • Potential benefits of combination therapy • Patient needs and views

  14. Immunomodulators and / or Immunosuppressants All act on the immune system specific or non-specific action Varied benefits and efficacy Main benefits in early, relapsing MS Long-term assessment ongoing Disease modifying therapies

  15. Immunomodulators • Immunomodulators • glatiramer acetate • beta interferons • Proven effectiveness in reducing relapse rates and severity • May slow accumulation of disability • Maximum benefits from: • Use in RRMS • Early and continuous treatment, some evidence for use in CIS • Prescribing in accordance with ABN Guidelines ABN Guidelines for the treatment of multiple sclerosis with Beta Interferons and Glatiramer Acetate ABN Mar 2007 (currently under revision)

  16. Glatiramer acetate Under ABN Guidelines and Risk Sharing Scheme May be used for relapsing-remitting MS for patients who can walk 100m having had two relapses in previous 2 years ABN Guidelines for the treatment of multiple sclerosis with Beta Interferons and Glatiramer Acetate ABN Mar 2007 (currently under revision)

  17. Beta interferons Under ABN Guidelines and Risk Sharing Scheme Interferon beta 1a & b May be used for relapsing-remitting MS for patients who can walk 100m having had two relapses in previous 2 years Interferon beta 1b May be used for patients with secondary progressive MS who can walk 10m aided or unaided who have relapses within the progression of their MS ABN Guidelines for the treatment of multiple sclerosis with Beta Interferons and Glatiramer Acetate ABN Mar 2007 (currently under revision)

  18. Cytokine production • MMP production • BBB disruption • CNS influx GA Th2 Mechanisms of Action Periphery Centrally BBB IFN b IFN  receptor Activation Passive decrease of CNS inflammation? IFN b Glatiramer Acetate • Active bystander regulation • Neuroprotection Th2 bias

  19. Glatiramer acetate • Mode of action differs from interferons • Changes proinflammatory Th1 cells into anti inflammatory Th2 cells • Well tolerated • Reduces relapse rate by 30% in RRMS • Reduces MRI burden of disease • Reduces black hole evolution • Long-term relapse data – 10 years Johnson KP et al. 1995 Neurology. 45(7):1268-1276 Johnson KP et al. 1998 Neurology. 50(3):701-708 Comi GC et al. 2001 Annals of Neurology. 49(3):290-297 Filippi M et al. 2001 Neurology. 57:731-733 Ford CC et al. 2006 Multiple Sclerosis. 12:309-320

  20. Glatiramer acetate • Effect on disability progression - much debate • Effect on neuroprotection - much debate • Does not exacerbate depression • 25 % find associated improvement in fatigue • No routine blood tests necessary Wolinsky JS et al. 2002 Neurology. 59:1284-1286 Ziemssen T et al. 2002 Brain. 125:2381-2391 Filippi M et al. 2001 Neurology. 57:731-733 Copaxone Summary of Product Characteristics March 2006

  21. Beta interferons • Interferon are naturally occurring proteins and play a crucial role in the functioning of the immune system • They are produced by a variety of cells in response to microbial stimuli • Block T cell activation • Inhibit the action of gamma-interferon and induce other substances to suppress the level of immune activity • Anti viral • Reduce relapse rate by around 30% The IFNB Multiple Sclerosis Study Group. 1993 Neurology. 43:655-661 Jacobs LD et al. 1996 Annals of Neurology. 39:285-294 The PRISMS Study Group. 1998 Lancet. 352:1498-1504

  22. Beta interferons • Reduce severity of relapses • Rapid suppression of MRI detectable disease activity (within 4 weeks) • Slows disability progression, but extent of this remains controversial • likely to be greatest where relapses are dominant feature (whether RRMS or SPMS) • As of August 2006, all products licensed for early use, still awaiting update of ABN guidelines for use of treatments in CIS. The IFNB Multiple Sclerosis Study Group. 1993 Neurology. 43: 655-661 Jacobs LD et al. 1996 Annals of Neurology. 39: 285-294 The PRISMS Study Group. 1998 Lancet. 352: 1498-1504 Jacobs LD et al. 2000 New England Journal of Med Medicine. 343: 898-904 European Study Group on Interferon-1b in Secondary Progressive MS. 1998 Lancet. 352: 1491-1497 Comi G et al. 2001 Lancet. 357: 1576-1582

  23. Neutralising Antibodies (NAbs) • All immunomodulators create antibodies • Antibodies developed by the beta interferons may neutralise effect of drug • Patients who develop NAbs are 60% more likely to experience relapses • Likely to occur 6-12 months after commencing therapy • It is suggested that all beta interferon patients should be tested for NAbs at 12-24 months • Ongoing debate about the influence of Nabs on treatment Sorensen PS et al. 2005 European Journal of Neurology. Nov;12(11):817-27. The PRISMS Study Group and the University of British Columbia MS/MRI Analysis Group. 2001 Neurology. 56(12):1628-36

  24. Comparable relapse rates Retrospective study undertaken in Argentina Carra A et al. 2003 Eur J Neurology. 10: 671-676 Khan 0 et al. 2002 CNS Drugs. 16(8): 563-578 Haas J et al. 2003 Presented at the AAN Annual Meeting, March 29-April 5, 2003 Honolulu, Hawaii

  25. DMT comparison table

  26. DMT side effect comparison table

  27. Interference with T-cell activation Yes Yes Decrease in Th1 and enhancement of Th2 cytokines Yes Yes Induces Th2 response Yes No Inhibits T-cell/BBB transmigration* No Yes CNS effects Yes No Neuroprotection Yes Indirect Antibodies Inert (Beneficial?) Neutralizing Glatiramer Acetate vs. Beta interferons Glatiramer Acetate Beta-Interferons *Critical differences Adapted with permission from Dhib-Jalbut S 2002 Neurology. 58:S3-S9

  28. When to change to second line treatment • This varies from centre to centre • There is no standardised pathway • There are some who are obviously still relapsing despite treatment, they would be considered for change • There maybe a need to repeat the MRI Scan to look for enhancing lesions • Consider NABs

  29. Tysabri (Natalizumab) • Natalizumab, a humanized monoclonal antibody • NICE approved • Modifies immune response by selectively inhibiting T cells from crossing the blood brain barrier, preventing these cells from migrating into chronically inflamed tissue • Indicated for treatment of highly active RRMS for: • patients with high disease activity despite treatment with beta-interferon/glatiramer OR • patients with rapidly evolving severe RRMS Tysabri Summary of Product Characteristics July 2006

  30. Tysabri - SENTINEL • SENTINEL (safety and efficacy of natalizumab in combination with Avonex (Interferon beta-1a)) • Two-year, randomized, multi-centre, placebo-controlled, double-blind study 1,200 patients with relapsing-remitting MS • Evaluated the effect of the combination of natalizumab and Avonex compared to treatment with Avonex alone in slowing the progression of disability and reducing the rate of clinical relapses • The primary endpoints for both Phase III two-year trials in MS was based on the Expanded Disability Status Scale (EDSS) and relapse rates. The pre-specified primary endpoint of the one-year analysis was relapse rates Rudick R et al. 2006 The New England Journal of Medicine. 354: 911-923

  31. Tysabri – study results • SENTINEL • The addition of TYSABRI to AVONEX resulted in a 54% reduction in the rate of clinical relapses over the effect of AVONEX alone (p<0.001). • met all secondary endpoints, including MRI measures • 67% of patients developed no new or newly enlarging T2 hyperintense lesions compared to 40 percent in the AVONEX plus placebo group (p<0.001) • On the one-year MRI scan, 96% had no gadolinium-enhancing lesions compared to 76% of AVONEX plus placebo-treated patients (p<0.001). • The proportion of patients who remained relapse-free was 67% compared to 46% percent in the AVONEX plus placebo-treated group (p<0.001) Rudick R et al. 2006 The New England Journal of Medicine. 354: 911-923

  32. Tysabri - AFFIRM • AFFIRM (natalizumab safety and efficacy in relapsing-remitting MS) • Two-year, randomized, multi centre, placebo-controlled, double-blind study 900 patients • Evaluated the ability of natalizumab to slow the progression of disability in MS and reduce the rate of clinical relapses • Reduced the rate of clinical relapses by 66% relative to placebo (p<0.001) • Met all one-year secondary endpoints, including MRI measures • 60% of patients developed no new or newly enlarging T2 hyperintense lesions compared to 22% of placebo-treated patients (p<0.001) • On the one-year MRI scan, 96% patients had no gadolinium enhancing lesions compared to 68% of placebo-treated patients (p<0.001) • The proportion of patients who remained relapse free was 76% compared to 53% in the placebo-treated group (p<0.001) Polman CH et al. 2006 The New England Journal of Medicine. 354: 899-910

  33. Immunosuppressants Mitoxantrone Cyclophosphamide Methotrexate Azathioprine Cyclosporine Used in aggressive disease Effective immune suppression Non-specific action High toxicity - immediate and long-term side-effects Immunosuppressants Ruiz-Pena JL & Izquierdo-Ayuso G 2002 Rev Neurol. Aug 16-31; 35(4): 373-80

  34. Immunosuppressants in MS • Azathioprine • used little in UK but more extensively in continental Europe • conflicting evidence of benefit • Mitoxantrone • cytotoxic drug - lymphoma/breast ca • licensed for progressive MS in US • Methotrexate • some evidence of benefit in SPMS, unlicensed Hommes OR & Weiner HL 2004 Journal of Neurological Sciences Aug 15; 223(1): 65-7

  35. Emerging treatments • Fingolimod (recommended for license in 2011) • Cladribine • Laquinimod • Alemtuzumab (Campath) • Teriflunomide • Oral fumarate (BG-12) • Stem cells

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