The field of multiple sclerosis (MS) has seen significant changes over the last several years [1, 2]. Clinicians and patients welcomed the introduction of disease-modifying therapy (DMT) for MS in the mid-1990s. Injectable agents, all with rather similar risk–benefit profiles, dominated MS care for over a decade. The approval of Natalizumab marked a change with the introduction of a more effective treatment option, but also entailed new risks associated with modulation of the immune system (e.g., risk of progressive multifocal leukoencephalopathy - PML) [2, 3]. More recently, the introduction of oral agents and new humanised monoclonal antibodies administered by infusion have opened yet another avenue for patients and clinicians [4]. Currently, there are over a dozen of DMTs available to treat MS, with varying availability around the world. Significant heterogeneity exists in the efficacy and risks associated with these therapies [5–7]. Therefore, clinicians have the challenge of tailoring treatment based on i) disease activity level (clinical and radiological data), ii) individual patient characteristics/preferences, iii) personal expertise/preference, in order to identify the optimal balance between efficacy and safety Table 1 (See Additional file 1 for data on some currently available agents) [8].

Table 1 Comparative adverse events of different DMTs [7, 8] Full size table

Risk stratification in MS

An understanding of the risk of untreated multiple sclerosis is crucial to make therapeutic decisions Table 2 [8]. In addition, physicians’ preferences and beliefs in effectiveness of treatment and drug safety profiles may influence their decisions. Disease activity/progression can be divided into physical, cognitive and radiological markers. Examples include number of attacks per year, number of disabling attacks, disability scales (clinical), lesion volume, GAD enhancing lesions, brain atrophy (MRI), and cognitive decline (e.g., using SDMT, PASAT, OR MoCA scales) [9]. Two scoring systems (Rio score and Modified Rio score) demonstrate good predictive value for MS progression. The Rio score includes MRI, clinical relapse and EDSS criteria, whereas the modified Rio score includes MRI and clinical relapse criteria (Fig. 1) [10]. A high risk profile using the modified Rio (score ≥2) includes either an MRI with more than 5 new T2 lesions (1 point) or 1 relapse in the first year (1 point) or two relapses within the first year of treatment (2 points) or the combination of these criterions [11]. These scores have been used to identify and predict response to Interferon β. For example, the modified Rio score in the PRISM trial revealed that participants who did not responded to Interferon β had a similar probability of disability progression as those assigned to the placebo group. Conversely, responders to Interferon β had a 52 % reduction in disability progression compared to placebo and non-responders (p < 0.0001). MS patients with a modified Rio score greater than or equal to 2 had a 65 % increased risk of disability progression (HR = 4.60; p < 0.001) [12]. A Canadian group concluded that a change in treatment may be considered in patients with relapsing remitting MS if there is a high level of concern in any one domain (relapses, progression or MRI), a medium level of concern in any two domains, or a low level of concern in all three domains [13]. The European Medicines Agency approves escalating therapy with Natalizumab or Fingolimod in patients who had at least one relapse in the previous year while on Interferon β and either ≥9 T2-hyperintense lesions on brain MRI or ≥1 contrast-enhancing lesion MRI activity alone after the first year of treatment was associated with three- to fivefold increased risk of relapses or disability compared with stable patients. These recommendations have been supported by several prospective studies [14, 15].

Table 2 Risks of untreated relapsing MS Full size table

Fig. 1 Modified with permission from Sormani et al. defining and scoring response to IFN‑β in multiple sclerosis. Nat. Rev. Neurol. doi:10.1038/nrneurol.2013.146 Full size image

Selection of a first line therapy will likely depend on several factors. Traditionally, and due to the availability of extended safety data, injectable agents may be the first choices. Given the comparable efficacy data between the injectable agents the selection of a therapy will be determined mostly by side effect profiles. Subjects with headaches, depression, and a history of liver dysfunction may experience worsening of these comorbidities when exposed to interferons. Monitoring for interferons includes following liver function tests, complete blood counts, and monitoring depression [8]. Given the availability of more effective drugs, the treatment paradigm is likely to change. However, it is expected there will be wide variability on the timing of this paradigm shift (e.g., starting more effective therapies as first line treatment) based on patients’ and physicians’ tolerance to risk, estimation of the clinical course, regional funding programs, among other factors. As a result, it is vital to identify situations for which physicians take the opportunity of escalating treatment when indicated (e.g., progression of disease determined by clinical relapses, EDSS disability score and imaging data).

Therapeutic inertia: a new paradigm in MS

Therapeutic inertia is a term introduced in 2006 to define the lack of treatment initiation or intensification in patients not at goals of care [16–19]. Some examples include failure to intensify treatment in patients with persistent elevated blood pressure or blood glucose [16, 20, 21]. Reasons to explain therapeutic inertia include the lack of training and cultural organization in the practice at “treating to target”, competing demands and clinical uncertainty [22, 23]. In the context of MS, therapeutic inertia is defined lack of treatment initiation or intensification when there is evidence of disease progression (based on clinical and radiological data). In the present study, disease progression was defined according to the modified Rio score, where patients had one or more recurrent attacks and/or an MRI with 5 or more new T2 lesions while receiving treatment with a disease- modifying agent [11]. Another more recent criterion strongly associated with risk of relapse or disability progression was the presence of isolated gadolinium-enhancing lesions [14, 15].