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Treatment escalation over induction therapy

Presented by
Dr Emmanuelle Waubant, University of California, San Francisco, USA
Dr Emmanuelle Waubant (University of California, San Francisco, CA, USA) discussed why treatment escalation is the preferred principle over induction therapy.

With respect to long-term outcomes in MS, there is a lot of heterogeneity. Patients can have different clinical and anatomical relapse locations, as well as different relapse frequency, severity, and recovery. Up to 20% of patients have “benign” disease, defined as having an EDSS ≥2.0 after 10-year duration. Although untreated MS may shorten life span by 6 years on average, many patients on moderately effective disease-modifying treatments (DMTs) have good outcomes in the long term. For example, it was shown that 69.8% of patients with clinically isolated syndrome on IFN-beta had EDSS <3.0 by year 11 [1].

Several clinical and MRI characteristics at onset predict poor outcome in cohorts, but not always in individual patients. Very little is known about the long-term safety and efficacy of oral and intravenous induction therapies. “For the treatment of classical MS, there is consensus that you have to start the therapy early, using either injectable or oral therapies”, Dr Waubant told. “Escalation is a very reasonable strategy, when there is breakthrough either clinically or on the MRI. In severe MS, early aggressive treatment using monoclonal antibodies is recommended.”
Progression and safety

IFN-beta, glatiramer acetate, and fingolimod were recently shown to decrease the risk of progression to secondary progressive MS, especially if initiated within 5 years of onset, Dr Waubant mentioned (HR 0.77; P=0.03; 5-year absolute risk of 3% vs 6% after follow-up of median 13.4 years) [2]. “So, early intervention is key. A nice meta-analysis has clearly shown reduced disability progression based on EDSS” [3]. Furthermore, recently published analyses showed that early escalation was associated with lower lifetime cost per patient, prolonged quality-adjusted survival, and longer median time to sustained increased disability [4,5].

In the short-term, there is an increased risk of auto-immune complications after initiating alemtuzumab. IFN-beta, glatiramer acetate, fingolimod, dimethyl fumarate, and natalizumab have all shown a good safety profile (if JC-virus-negative). There is limited long-term data (i.e. >5 years) for haematopoietic stem cell therapy (HSCT), alemtuzumab, ocrelizumab, and cladribine.
In contrast: induction therapy

Induction therapy often means first-line treatment with the goal of increasing the rate of complete remission. However, no currently available MS drug induces complete remission. Rates of no evidence of disease activity (NEDA) are quite low, according to Dr Waubant. Natalizumab was associated with 34% NEDA at year 2, alemtuzumab with 40% NEDA at year 5, and autologous HSCT (open label) with 60% NEDA at year 5. Patients who achieve NEDA often have a less active initial disease, whereby induction therapy was not needed [6]. Prior informative studies did not involve early MS, had a relatively short follow-up (<3 years) and small sample size, and were not always randomised with a control group. On top of this, they focused on early effect, not what happened years after discontinuing treatment.

Early initiation of traditional DMTs is effective and safe for most patients with clinically isolated syndrome or relapsing-remitting MS. Carefully monitoring these patients clinically and with yearly MRI is important to detect possible breakthrough. In case of disease activity, early escalation using more effective agents has proven beneficial. Data on true induction therapy with long-term safety and efficacy are not yet available.

  1. Kappos L, et al. 2016;87:978-87.
  2. Brown JWL, et al. JAMA. 2019;321:175-187.
  3. Signori A, et al. Mult Scler Relat Disord. 2016;6:57-63.
  4. Furneri G, et al. BMC Health Serv Res. 2019;19:436.
  5. Harding K, et al. JAMA Neurol. 2019;76:536-541.
  6. Prosperini L, et al. J Neurol Sci. 2016 May 15;364:145-7.

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