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Journal Club Brehan King October 13, 2004

Introduction . Multiple sclerosis: an acquired, chronic, demyelinating dz of the CNS2 Main Types: relapsing-remitting and chronic progressiveIncidence varies among different populations, 1.5-11/100,000Symptoms usually begin btwn ages of 15 and 50 yrsWomen>Men. Multiple Sclerosis. Etiology: ini

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Journal Club Brehan King October 13, 2004

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    1. Journal Club Brehan King October 13, 2004 Effect of Early Treatment on Conversion to Definite Multiple Sclerosis: a Randomised Study The Lancet Vol 357 May 19, 2001

    2. Introduction Multiple sclerosis: an acquired, chronic, demyelinating dz of the CNS 2 Main Types: relapsing-remitting and chronic progressive Incidence varies among different populations, 1.5-11/100,000 Symptoms usually begin btwn ages of 15 and 50 yrs Women>Men

    3. Multiple Sclerosis Etiology: initiating event unknown, dz involves autoimmune-mediated inflammatory demyelination and axonal injury Pathology: perivascular infiltration by lymphocytes and monocytes CSF: increased IgG in CNS, oligoclonal bands, increased Abs to myelin basic prot

    4. Symptoms of MS Unilateral visual impairment Double vision Paresthesias Ataxia or unsteadiness Vertigo Fatigue Muscle weakness Urinary disturbance Dysarthria

    5. Signs of MS Optic neuritis (pain and blindness) Internuclear ophthalmoplegia Nystagmus Spasticity or hyperreflexia Babinski sign Absent abdominal reflexes Dysmetria or intention tremor Impairment of central sensory pathways Labile or changed mood

    6. Differential Diagnosis for Relapsing-Remitting MS Vascular dz: strokes, vasculitis Behcets Syndrome Systemic Lupus Erythematosus Sarcoidosis

    7. Treatments Glatiramer acetate (Capaxone): myelin-like polypeptide, inhibits cellular immune rxns, daily SC inject Interferons IFN-beta-1a (Avonex), weekly IM inject IFN-beta-1b (Betaseron, Rebif), Q other day SC inject Side effects: flu-like syndrome, local inflamm rxns at inject sites

    8. Treatments cont. Acute attacks: IV methylprednisolone followed by prednisone taper Shortens acute exacerbations

    9. So, what is the evidence for these treatments and when should they by started? Does Making an Early Diagnosis Matter?

    10. CHAMPS and ETOMS 2 Studies suggest a role for starting IFN treatments before clinically definite MS is diagnosed: CHAMPS NEJM Sep 2000 ETOMS Lancet May 2001

    11. Clinically Definite MS Defined by the occurrence of at least 2 neurological events consistent with demyelination Separated anatomically in the CNS and temporally MRI-identified lesions consistent with neurolog events adds certainty to diagnosis

    12. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised trial The Lancet Vol 357 May 19, 2001

    13. So, why did researchers think early intervention would be a good thing to study?

    14. Background Previous studies of IFN-beta treatments have demonstrated benefits for patients with established MS (slowed progression of disability, decreased rate of relapses, decreased brain lesions on MRI) Studies have also shown that axonal damage occurs more rapidly in the early phase of MS Ultimately, axonal damage leads to the irreversible neurological deficits that cause disability Given this info, earlier treatments may have the greatest impact

    15. ETOMS A double-blinded, randomised, placebo-control trial Follow up to the CHAMPS trial which showed early treatments with IFN-beta-1a at first demyelinating event is beneficial for patients with brain lesions on MRI that indicate high risk of clinically definite MS

    16. Methods Patients were randomly assigned 22 micrograms IFN-beta-1a or placebo SC injections 1X/week for 2 yrs Treatment was started on patients with a first episode suggestive of MS within the preceding 3 mos and strongly suggestive MRI findings

    17. Patients Ages 18-40 yrs Clinical syndrome indicating unifocal or multifocal CNS involvement Presented with a 1st neurological episode suggestive of MS in preceding 3 mos At least one neurological abnormality on neurological physical exam

    18. MRI scans of selected patients At least 4 white matter lesions on T2-weighted scans OR At least 3 white matter lesions if at least one was infratentorial or enhancing after injection with Gd-DTPA

    19. Methods cont. Steroid treatments for exacerbations were allowed for moderate or severe exacerbations Exclusions: any previous immunosuppressive or modulatory Txs, participation in any experiment procedures <1yr, other serious systemic illness or psych disorders, pregnancy, unwillingness to use reliable contraception

    20. Enrollment 57 centers in 14 European countries 8/95-7/97 enrollment period Computer-generated randomisation Patients underwent complete physical and neurological exams Disability was rated on 1. Expanded disability status scale (EDSS), 2. Scripps neurological rating scale (SNRS), 3. Ambulation Index

    21. Methods cont. Additional testing, when indicated, was performed on selected pts to rule out other causes eg. Lyme serology All pts received baseline MRI

    22. Treatment and Monitoring Pts randomly assigned to the 2 groups (Interferon beta and placebo) Each study site provided a treating Dr. (responsible for overall mgmt of pt) and an evaluating Dr. (responsible for scheduled neurological exams and exacerbation follow-up visits) Brain MRIs were performed as part of pre-study screening and at end of months 12 and 24

    23. Outcomes Primary: Conversion to clinically definite MS (CDMS) Secondary: Change in SNRS scores Time to 2nd exacerbation MRI measures (#T2 active lesions, # enhancing T1 lesions, # of pts without MRI activity, yearly changes in hyperintense T2 lesion volume)

    24. MRIs Each patient had same MRI study performed All scans were sent to Milan and reviewed centrally If necessary, poor studies were repeated Same readers were used for follow-up scans Strict definitions were used for new and enlarging lesions

    25. Statistical Methods Sample size calculated based on epidemiological studies, 40% of pts in placebo group expected to convert in 2yrs Assumed that 20% of treated pts would convert, 90% power Assumed a 20% drop-out rate Calculated that 155 patients/group necessary

    26. Statistical Methods cont. Pts who withdrew before reaching primary end point were classified as exacerbation-free Used logistic regression analysis with adjustments for country and other factors found to be signif predictors of conversion to derive the odds ratio btwn groups, adjustment did not influence results Factors predictive of conversion included time btwn first attack and onset of treatment, T2 lesion # at screening, and multisymptomatic onset

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