Don’t start treatment too late

Don’t leave it too late before you start Treatment,

How much more evidence do we need?

Chalmer T, Baggesen LM, Nørgaard M, Koch-Henriksen N, Magyari M, Sorensen PS; Danish Multiple Sclerosis Group.Early versus later treatment start in multiple sclerosis a register based cohort study. Eur J Neurol. 2018 May 30. doi: 10.1111/ene.13692. [Epub ahead of print]

OBJECTIVE:To assess long-term treatment effectiveness of disease-modifying therapy (DMT) initiated in early disease course versus later treatment start.
METHODS:We included all Danish multiple sclerosis (MS) patients treated with DMT through two nationwide population-based MS registries. Patients were categorized as early treated if treatment started within two years after the first MS symptom (n=2,316) and later treated patients if treatment started between two and eight years after clinical onset (n=1,479). We compared time from treatment start to progression to Expanded Disability Status Scale (EDSS) 6 and mortality between cohorts as hazard ratio (HR) using a Cox proportional hazards model with adjustment for stabilized inverse probability of treatment weights. Several sensitivity analyses were conducted.
RESULTS:Median follow-up time of 3,795 patients was 7.0 years (range 0.6-19.5) for the EDSS 6 outcome, and 10.4 years (range 1.2-20.1) for the mortality outcome. Patients with later treatment start showed 42% increased hazard rate of reaching EDSS 6 compared with the early treated patients (HR 1.42; 95% CI 1.18-1.70; p<0.001). When stratified by sex the increased hazard among later treated women persisted (HR 1.53; 95% CI 1.22-1.93; p<0.001), while the HR was lower in men (1.25; 95% CI 0.93-1.69; p=0.15). Mortality was 38% increased in later starters (HR 1.38; 95% CI 0.96-1.99; p=0.08).
CONCLUSION:Patients who started treatment with DMT later had shorter time to reaching EDSS 6 compared with patients who started early, and the delay showed a tendency to shorten time to death. Our results support the use of early treatment.

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  • Disability progression
    The probability of reaching EDSS 6 is seen in figure 2, showing a lower probability of reaching EDSS 6 among early treated patients compared with patients treated later. A total of 480 patients (12.7%) reached EDSS 6 during the entire follow-up, 10.2% of early treated
    patients during a median follow-up of 7.0 years vs. 16.5% of later treated patients during a median follow-up of 6.9 years.

    Does this pass the smack in the eyes test?

    This number are in line with order lower studies that use even more potent drugs

    At a median time of 16.8 years after disease onset, 10.7% (95%
    confidence interval [CI]57.2–14%) of patients reached an EDSS 6, and 18.1% (95% CI513.5–22.5%) evolved from
    relapsing MS to secondary progressive MS (SPMS).

    Although we did
    not find that treatment escalation reduced the risk of further
    disability progression, it is possible that active management
    with DMTs influenced the overall favorable
    outcomes. Patients experiencing clinical relapses or radiologic
    worsening were more likely to undergo treatment
    escalation. Nonetheless, clinically significant disability
    accrued in 59% of subjects, illustrating a remaining
    unmet need for more effective DMTs in RMS, and any
    effective therapy for progressive MS

    Earlier natural history studies found that up to
    54% of RMS patients transitioned to SPMS after a
    median time of 19 years.38–40 With a median time of
    16.8 years since disease onset, we would have anticipated
    that between 36% and 50% of the RMS patients would
    have developed SPMS, whereas only 11.3% of this

    cohort transitioned to SPMS during the course of the
    study. This transition rate of 1% annually is lower than
    reported from natural history studies but similar to a
    more recent retrospective analysis in an IFN-treated population.

    Similarly, an increase in the EDSS score over 2
    years was not associated with worse long-term prognosis.
    Thus, short-term increases in EDSS do not necessarily
    predict future accumulation of disability in RMS patients
    over the longer term, a conclusion also reached in a
    pooled analysis of patients randomized to placebo arms
    in 31 clinical trials.48 Because neither clinical nor radiographic
    features over 2 years had predictive value, it is
    not surprising that the combined measure of these variables,
    NEDA, was also not associated with long-term disability

    Long-Term Evolution of Multiple Sclerosis
    Disability in the Treatment Era

    ANN NEUROL 2016;80:499–510


  • Requires prompt, accurate diagnosis to truly mean anything! First relapse in 2014 when an orthopaedic surgeon told me I had a degenerative disc and other symptoms such as wobbly walking were "a nerve being tickled" as MRI had shown no nerve impingement. Diagnosis with second relapse – FOUR years later.

    Yes please let the medical world take on board neurologists request here in the uk (and internationally) to refer promptly and yes treat early. But my point about swift, accurate diagnosis is still valid!

  • I must say it is very confusing to read about the early treatment guideline literally everywhere, only then to be faced as a real life patient with a real life MS consultant/researcher who sits on the fence about it, as i did.

    Is there definitive evidence that all MS patients will definitely benefit from DMTs? What about the significant percentage of patients in the 30 year study from UCL neurology who appeared to have benign or stable MS? Would it make sense to sacrifice the possibility of DMT side effects for this section of patients who would turn out never to need it, in order to catch the other percentage who may benefit from the DMTs?

    My point is, that to say early drug intervention is the silver bullet seems overly simplistic as I believe that MS is a multi factoral disease with varying inital causes for different individuals. These varying causes then impact the disease path in accordingly variable ways and the 'disease' should always be handled on an individual basis.

    • I've heard a lecturer recently (who may or may not be a bit of a renegade), claim that up to 90% of clinics, which I suspect he meant in the USA, DO NOT follow recent guidelines for diagnosing or for treating Multiple Sclerosis.

      Which somewhat supports my suspicions and what I tell anyone who comes to me for advice if they are troubled by thoughts that they might have Multiple Sclerosis… get away from a general neurology service, where most of their doctors seem stuck in whatever they learned 20 or more years ago in medical school, and get into a specialist MS Center, where it would be hoped that at least peer pressure to keep up on research and guideline changes occurs.

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