In this issue of CJNS, the Canadian Multiple Sclerosis Working Group (CMSWG) unveil a contemporary edition of Treatment Optimization Recommendations (TOR).^{Reference Freedman, Devonshire and Duquette1} Similar to a geographical tor or summit, the TOR are a culmination or peak of current knowledge in multiple sclerosis (MS). This collaborative effort is a guide written by expert clinicians based on available evidence rather than formal clinical practice guidelines. The intent of the TOR is to help neurologists navigate treatment decisions in a shared decision-making process with individuals with MS.

Since the original CMSWG recommendations in 2004, the objective has been to develop practical recommendations to empower neurologists to assess response to disease-modifying therapy (DMT) and make an informed decision regarding change in treatment to optimize outcome.^{Reference Freedman, Patry, Grand’Maison, Myles, Paty and Selchen2} The original recommendations were based on a model assessing response to DMT in three domains: relapses, progression, and magnetic resonance imaging (MRI) outcomes.^{Reference Bashir, Buchwald and Coyle3} This clinically practical model was developed to apply to the first agents (interferon-β and glatiramer acetate) shown to change the natural history of relapsing MS.^{Reference Freedman, Patry, Grand’Maison, Myles, Paty and Selchen2} Over the next decade, there was a rapid expansion in DMT options for relapsing MS. In response, the revised CMSWG recommendations in 2013 introduced the concept of evaluating treatment response to inform switching DMT to a lateral treatment versus escalation treatment.^{Reference Freedman, Selchen and Arnold4}

The current CMSWG recommendations provide guidance in the increasingly complex landscape of MS treatment.^{Reference Freedman, Devonshire and Duquette1} As DMT options increase for relapsing MS, it is clear that key points include (1) recommending treatment initiation soon after diagnosis, (2) performing risk stratification to inform initial DMT selection, and (3) re-evaluating at regular intervals to enable escalation of therapy for suboptimal treatment response. There is increasing evidence that early initiation of therapy results in improved long-term outcome.^{Reference Chalmer, Baggesen, Norgaard, Koch-Henriksen, Magyari and Sorensen5} Striving to initiate DMT early in the disease course is facilitated by the updated McDonald criteria which enable earlier MS diagnosis.^{Reference Thompson, Banwell and Barkhof6} While some individuals have risk factors favoring a high-efficacy therapy as initial DMT, the most common treatment course remains initiation of a platform therapy with an escalation approach for suboptimal response. High-efficacy therapies (alemtuzumab, cladribine, fingolimod, natalizumab, and ocrelizumab) have greater efficacy but a more substantial side effect profile than platform therapies (dimethyl fumarate, glatiramer acetate, interferon-β, and teriflunomide). It is worth noting that there is mounting evidence that starting a high-efficacy therapy as initial DMT is associated with improved long-term outcome.^{Reference Harding, Williams and Willis7,Reference Brown, Coles and Horakova8} At this point, the optimal approach (initial high-efficacy therapy versus escalation therapy) for the majority of individuals with relapsing MS remains an unresolved debate.^{Reference Burton and Traboulsee9} If an escalation approach is adopted, then it is important to adjust treatment for suboptimal response and not fall into therapeutic inertia.^{Reference Saposnik, Montalban and Selchen10}

An exciting new addition to the current CMSWG recommendations is the introduction of DMT for progressive forms of MS. Ocrelizumab has demonstrated a benefit in disability progression for primary progressive MS among individuals aged 18–55 years with ~25% having gadolinium-enhancing lesions at baseline.^{Reference Montalban, Hauser and Kappos11} Siponimod has demonstrated a benefit in disability progression for secondary progressive MS among individuals aged 18–60 years with active inflammatory disease.^{Reference Kappos, Bar-Or and Cree12} Given that the mechanism of these medications is believed to be immunomodulatory, it is likely that these medications will be most beneficial early in progressive MS while there is active inflammatory disease.

Although the current CMSWG recommendations provide advice on when to consider switching therapy based on major/minor criteria for evaluating relapses and MRI activity, the optimal goal for MS disease activity remains unclear. No evidence of disease activity (NEDA) is most commonly defined as absence of relapses, progression measured by Expanded Disability Status Scale (EDSS), and new/enlarging MRI lesions.^{Reference Parks, Flanagan, Lucchinetti and Wingerchuk13} Although NEDA is difficult to achieve, it remains inadequate in communicating the manifestations and pathophysiology of MS. Additional considerations include cognition, brain/spinal cord atrophy, and biomarkers. While cognition should be evaluated with a tool such as the Symbol Digit Modalities Test, there is insufficient evidence that changing DMT will improve cognitive decline and switching DMT for this indication should be avoided. Brain and spinal cord atrophy are emerging indicators of disease severity but it is premature to recommend use in routine clinical practice given lack of standardization in image acquisition and interpretation. Biomarkers, particularly neurofilament light chain, are an emerging measure of disease activity but it is premature to recommend biomarker testing to guide clinical practice. Despite NEDA being inadequate to express the breadth of MS, it is uncertain whether NEDA versus minimal evidence of disease activity result in different long-term outcome.^{Reference Prosperini, Mancinelli and Haggiag14}

This version of the CMSWG recommendations considers treatment throughout the life cycle including pediatric-onset MS, family planning considerations, and among older adults with MS. All of these topics are emerging areas with sparse high-quality evidence for the basis of treatment decisions. As more individuals with MS are treated with high-efficacy therapy, the issue of immunosenescence is of increasing importance. The current recommendations suggest that consideration may be given to discontinuation of DMT among individuals aged >60 years with a period of clinical stability. Among a group of patients aged >60 years who discontinued DMT, ~90% remained off therapy although it is important to note that 80% were receiving a form of platform therapy (66% injectable, 14% oral) at the time of DMT discontinuation.^{Reference Hua, Fan, Conway, Thompson and Kinzy15}

Recently, the American Academy of Neurology (AAN) released practice guidelines concerning DMT for adults with MS.^{Reference Rae-Grant, Day and Marrie16} These evidence-based recommendations on starting, switching, and stopping DMT are based on the results of a systematic review, and all recommendations are assigned a quality of evidence rating. The AAN practice guidelines are a useful compliment to the CMSWG TOR. The purpose of the TOR is not to duplicate these practice guidelines but provide a framework to guide clinical decision-making based on informed expert advice.

Personally, I find the CMSWG TOR a very practical tool in reflecting on my own practice and one that will be of use in navigating future treatment discussions with patients in the MS clinic. I believe that other clinicians who treat individuals with MS will be of a similar opinion. The TOR are a pinnacle of teamwork with current evidence and expert opinion culminating in a resource for other clinicians both nationally and internationally. In the evolving landscape of MS therapy, I foresee that as this edition of TOR is released that the next TOR is on the horizon.