Treatment Optimization in Multiple Sclerosis: Relapses

1
Treatment Optimization in Multiple Sclerosis
Relapses

• Dr. Daniel Selchen
• Director Neuroscience Musculoskeletal Health
  System
• Trillium Health Centre
• Consultant Neurologist
• Multiple Sclerosis Clinic
• St. Michaels Hospital

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Relapse Definition International Panel on the
Diagnosis of Multiple Sclerosis (McDonald)

• An attack (exacerbation, relapse) refers to an
  episode of neurologic disturbance of the kind
  seen in MS, when clinicopathologic studies have
  established that the causative lesions are
  inflammatory and demyelinating in nature.

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Relapse Definition International Panel on the
Diagnosis of Multiple Sclerosis (McDonald)

• For general diagnostic purposes, an attack
  should last for at least 24 hours
• In defining what constitutes separate attacks
  it was agreed that 30 days should separate the
  onset of the first event from the onset of the
  second event.

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Problems and Issues

• Are relapses a major factor in long term outcome
  of MS patients?
• Does preventing relapses influence disease
  progression?
• What do we compare relapse outcomes to
• Natural history
• Clinical trial results
• Patients history

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Problems and Issues

• Are all relapses the same?
• Are relapses the tip of the iceberg?

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Problems and Issues

• For every clinical relapse, gt10x as many MRI
  relapses
• The tip of the iceberg or straw that broke the
  camels back phenomenon

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Do relapses matter?

• Weinshenker suggests a weak correlation between
  early attack rate and disease progression.
• Confavreux (2000) suggest that attacks are
  important only up to an EDSS of 4.0.
• Lublin (2000) suggests that attacks increase
  disability.
• Ebers (2002) suggests that in the long-term
  attacks probably have no influence.
• Filippini et al. (2003) suggest that the evidence
  for modification of relapse rate with IFN is
  marginal after one year

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Predictive Value of Relapses on Time to
Disability Progression (EDSS)
ATTACKS
TIME (
yrs) to
TIME (
yrs) to
st
in 1
2 YRS
EDSS 6 (cane)
EDSS 8 (w/c)
1
20
36
2
17
28
3
18
28
4
13
24
5
7
14
Weinshenker BG, et al. Brain. 19891121419-1428.
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Relapses and the Degree of Persistent Disability

• Database of pooled placebo patients from clinical
  trials 224 pt.
• 42 of pt. had residual deficit of at least 0.5
  EDSS
• 28 had residual deficit of gt0.5 EDSS at an
  average of 64 days
• Lublin FD et al
  NEUROLOGY2003611528

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Relapses Significance

• Relapses are significant to patients early in the
  course of the disease because of short term
  disability, lifestyle, and psychosocial issues,
  and are worth treating

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Relapses Significance

• The possibility that suppression of early
  clinical and subclinical attacks may modify the
  course of MS is the cornerstone of our rationale
  for early treatment but is not at this time
  supported by good evidence

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Recommendations for determining level of concern
with regard to treatment modification based on
relapse outcome

• Current status Gestalt no clear guidelines
• Proposed model based on
• Relapse rate
• Relapse severity
• Recovery from relapse

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Recommendations for determining level of concern
with regard to treatment modification based on
relapse outcome

• Rate
• Trials with DMTs show 29-33 reduction in relapse
  rate. Trial data may not be generally applicable
  as the patients in the pivotal trials were
  characterized by long duration of disease, high
  relapse rate, low EDSS

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Recommendations for determining level of concern
with regard to treatment modification based on
relapse outcome

• Rate
• Clinical trial data suggest annual relapse rate
  of 1.0
• Regression to the mean
• Relapse frequency declines with time
• Natural history data suggest annual relapse rate
  of 0.4
• Relapse rate data may reflect pattern of follow up

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Recommendations for determining level of concern
with regard to treatment modification based on
relapse outcome

• Relapse rates fall with less frequent observation
  (Thygesen)
• Q 3 weeks 1.2
• Q 3 months 0.5
• Q 6 months 0.3
• Q 12 months 0.2

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Recommendations for determining level of concern
with regard to treatment modification based on
relapse outcome

• Severity
• Is relapse severity a meaningful measure?

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Strategically Placed Lesions Lead to Clinical
Attacks
Disruptive Lesions
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Recommendations for determining level of concern
with regard to treatment modification based on
relapse outcome

• Severity
• There is evidence that polysymptomatic and motor
  relapses correlate with worse prognosis
• More severe relapses disruptive for patient

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Recommendations for determining level of concern
with regard to treatment modification based on
relapse outcome

• Recovery
• Runmarker (1993) degree of remission after last
  relapse had prognostic significance at 5 years
  post disease onset
• Majority of relapses improve within 3 months

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Recommendations for determining level of concern
with regard to treatment modification based on
relapse outcome

• Evidence for the efficacy of DMTs focuses
  predominantly on relapse number and severity.
• With individual patients, the only clear measure
  of efficacy is comparison of the baseline relapse
  rate over the 2 years prior to DMT initiation to
  the annual relapse rate while on active Rx.

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Recommendations for determining level of concern
with regard to treatment modification based on
relapse outcome

• Rate
• Comparison to patient baseline (preferably
  prospective)
• Obviously problematic in short term in patients
  with low relapse rate
• Implications for treatment follow up

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Recommendations for determining level of concern
with regard to treatment modification based on
relapse outcome

• Severity
• Effect on ADLs
• Steroid use
• Hospitalization
• Uni vs. polysymptomatic
• Motor, cerebellar

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Recommendations for determining level of concern
with regard to treatment modification based on
relapse outcome

• Recovery
• Prompt recovery ( 2/3)
• Improve between 3 and 12 months (22)
• Improve between 6 and 12 months (10)
• Lublin (2000) incomplete relapse recovery
  resulted in sustained neurological deterioration

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Determining the level of concern to consider
treatment modification based on relapse outcomes
Rate of change is relative to the baseline.
Reference time frame for baseline ? 2 years prior
to treatment initiation.
Ideally, prospective and objective relapse data
should be obtained during the reference period
(minimum 6/12)
Freedman et al, Can J Neurol Sci 31157 (2004)
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Suggestions

• Regular reassessments of patient conditionkey to
  adherence and ability to assessresponse to
  therapy
• Recommended schedule
• Q 3 months during first year of treatment
• Q 6 months or yearly thereafter

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Suggestions

• If resources allow, regular telephone contact
  with patients (e.g., every 3 months), if
  physician visits not feasible, to try to capture
  true relapse data.
• A system of standardized patient diaries.
• A government/insurer sponsored long-term registry
  of all consenting patients on DMTs to facilitate
  better understanding of the clinical importance
  of relapses as well as the long term benefits of
  DMTs