Comment by Dr. Michael Yeung
NeuroSens survey on sequencing – Part 2

Clinicians managing a newly-diagnosed patient with relapsing multiple sclerosis are faced with a welter of treatment options. In the past few years in Canada, platform therapies have expanded from the injectable BRACE to an injectable/oral CABARET: Copaxone, Avonex, Betaseron, Aubagio, Rebif, Extavia and Tecfidera.

In addition, there are new formulations of Copaxone (administered three times/week) and Avonex (Plegridy, administered subcutaneously q14 days). (Additional first-line options exist in other countries.)

Traditionally, the goal of initiating a disease-modifying therapy (DMT) has been to reduce the risk of relapses. In part this was because relapse reduction was the most demonstrable benefit in clinical trials; relapses are also the most likely clinical endpoint to be assessed in practice. All of the approved DMTs modulate the dysfunctional immune response in MS through various mechanisms (see Part 1 of this series), and all have demonstrated a significant reduction in relapse rates in pivotal trials. The benefit of relapse reduction is supported by natural history studies, which have shown that relapse frequency in the first two years after diagnosis is prognostic of a shorter time to fixed disability milestones (Scalfari et al. Brain 2010;133:1914-1929; Binquet et al. Neuroepidemiology 2006;27:45-54). The prognostic value of relapses appears to be minimal after five years (Tremlett et al. Neurology 2009;73:1616-23).

Counting relapses has its limitations. Earlier diagnosis has meant that relapse frequency is often low at presentation, and is therefore a less useful indicator of disease severity; and infrequent clinic visits means that relapses are less likely to be recorded by the clinician or recalled by the patient. More qualitative features may be more important, such as relapse severity, an indication of the aggressiveness of the individual’s immune response; lesion location (sphincteric, motor, cerebellar or brainstem involvement), which are associated with a higher risk of disability; a shorter inter-attack interval; and residual deficits, which may provide an indication of the individual’s ability to heal (Bergamaschi et al. J Neurol Sci 2001;189:13-21; Mowry et al. Neurology 2009;72:602-8). Signs of more widespread involvement, such as multifocal attacks, also have a poorer prognosis (Runmarker & Andersen. Brain 1993;116:117-34).

These features, along with demographic factors such as patient age and ethnicity, provide some measure of an individual patient’s risk of disability. However, unlike what is seen in other areas of medicine, the importance of one factor relative to another is not known; prognostic factors cannot be scored to provide an individual risk profile. Moreover, a full assessment – including a neurological examination, MRI (lesions, atrophy), and use of assessment tools (EDSS, Timed 25-Foot Walk, neurocognitive testing) – is not routinely done in many practices.

So in a clinical setting, identifying those at-risk is likely based on the individual patient’s “gestalt”, as has been described for identifying treatment failure (Freedman et al. Can J Neurol Sci 2004;31:157-168). This relies on inductive reasoning, which can only provide a sense of the probability (rather than the certainty) of an outcome; but such is the art of medicine, and this may be a reasonable approach given the uncertainties of the MS disease course. However, it means that it is all the more urgent to respond promptly if there are signs of breakthrough disease.

A further consideration when selecting an initial treatment is more pragmatic: what initial treatment is the patient likely to accept? Is it more rational to initiate any therapy to start patients along the treatment path, or to select a potentially more efficacious therapy but one that a patient is less likely to tolerate or accept?

As a general rule, clinicians choose the more conservative approach, favouring safety rather than efficacy. This may be a holdover from the past when the four injectable options were viewed as comparably effective. As a result, injectables continue to be prescribed more often than orals as the first-choice agent. To date, the few head-to-head studies comparing first-line orals with the injectables, such as the CONFIRM and TENERE trials, have produced equivocal results (Fox et al. N Engl J Med 2012;367:1087-1097; Vermersch et al. Mult Scler 2014;20:705-716). This may help to explain why glatiramer acetate continues to be the most frequently prescribed injectable, despite the fact that it is the only DMT not indicated to slow disability progression. The key advantages of injectables are the availability of long-term safety data, and habit.

Prescribing patterns do change and first-line orals (teriflunomide, DMF) are now the initial treatment choice for many patients. Teriflunomide is generally well-tolerated, but patients may object to adverse effects such as hair thinning, the need for frequent blood monitoring, and the need for effective contraception. The use of DMF may be limited by poor tolerability, notably flushing and gastrointestinal symptoms, and the risk of persistent lymphopenia, reported to occur in 29% of patients after drug discontinuation (Spinelli et al. ECTRIMS 2016; abstract P703). A recent study found that once lymphopenia (grade 2 or worse) developed, lymphocyte counts did not normalize unless DMF was discontinued (Longbrake et al. Mult Scler J Exp Transl Clin 2015;1:pii:2055217315596994).

The high rate of glatiramer acetate prescribing may be explained in part by its safety in pregnancy. This suggests a working assumption that younger women with MS are likely to become pregnant at any time. In a recent analysis in the U.S. for the period 2006-2014, about 12-14% of women with MS aged 25-29 years, and 10-12% of women aged 30-34 years became pregnant (Houtchens et al. ECTRIMS 2016; abstract P854). The overall pregnancy rate for all ages was < 3%.

With the expanding therapeutic armamentarium, an issue of increasing importance is the long-term treatment plan. Will a clinician’s initial choice of a given therapy limit his/her treatment options later on? Three key issues may be especially significant: lymphopenia; elevated liver enzymes; and the need for a washout period.

As noted above, moderate-to-severe lymphopenia may persist in a small proportion of DMF-treated patients and may require drug discontinuation; in the integrated analysis of phase III data, grade 3 lymphopenia persisting >6 months was reported to occur in 2.5% (Fox et al. ECTRIMS 2016; abstract P716). The concern in such a scenario is that there are no ideal next choices: higher-efficacy agents that lower lymphocyte counts (e.g. fingolimod, alemtuzumab) may not be advisable; and the use of natalizumab in an immunosuppressed patient may be associated with an increased risk of progressive multifocal leukoencephalopathy (PML). So the options may be limited to initiating an injectable agent, or interrupting therapy until lymphocyte counts recover. Elevated liver enzymes may be a further cause for concern, so there may need to be a washout period or, in the case of teriflunomide, an active elimination protocol until liver enzymes normalize.

Ideally, the washout period would be as short as possible, but not only to reduce the risk of increased disease activity while the patient is off therapy. Drug interruptions break the habit, already tenuous, of regularly taking a medication and may compromise patient adherence to the regimen. This was seen in an analysis of the Ontario Drug Benefit database for the period 2006-2008 (Wong et al. Can J Neurol Sci 2011;38:429-433). A majority of MS patients stopped their initial DMT within two years. More importantly, less than 10% of those who discontinued subsequently started another treatment. Since that time, the availability of oral DMTs, improved injection devices and new formulations of injectable agents may have lowered the proportion of patients who stop treatment. But the results sound a note of caution. The hidden cost of treatment failure/intolerability is a proportion of patients who will conclude that MS treatments don’t work for them, they’re too much trouble, or they didn’t really need therapy after all. Thus, they join the ranks of the estimated one-third of treatment-eligible MS patients who are untreated.

Treatment failure and escalation will be discussed in Part 3 of our series.

Comment
Dr. Michael Yeung: The introduction of several new treatment options for relapsing multiple sclerosis, and the addition of several more over the upcoming years, have made initial therapeutic choices increasingly complex for the clinician and the patient.  As Dr. Freedman noted in Part 1, the choice of treatment would be easier if we understood which putative immune mechanism was in play in any particular patient at any particular time of the disease course.

The initial choice of therapy is predicated on multiple factors, including (but not limited to):

1. Patient’s acceptance of the diagnosis and willingness to commence treatment
2. Patient’s preference for injections vs. oral formulations
3. Patient’s life choices and adherence (e.g. willingness to get bloodwork; when and if to start a family)
4. Patient’s risk tolerance
5. Use of “natural” supplements and remedies
6. The gestalt of the clinical and radiological presentation
7. Physician’s experience with, and preference for, the different therapies
8. Physician’s risk tolerance
9. Understanding of the mechanism of action of the DMTs

As our therapies become more effective, closer surveillance of the patient becomes more important to adjust therapy appropriately. This may require an increased number of clinic visits to monitor for relapses and progression, as well as a more comprehensive evaluation looking for objective measures of disease change.

Monitoring for side effects, particularly immune-mediated issues, can be time-consuming.  We continue to learn about these “real-world” effects: some have been unexpected as exposure and duration of use of these medications increase.

With modulation of the immune system, successive therapeutic alterations increase in complexity, especially if there are changes in lymphocyte counts and/or lymphocyte subsets. Careful consideration of these factors may provide guidelines for appropriate treatment sequencing. Available evidence is low, and “best opinion” may be all that is available to guide treatment decisions.

NeuroSens survey on sequencing – Part 2

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