Multiple sclerosis (MS) is a chronic disease of the central nervous system characterised by inflammation, demyelination, glial scar formation and axonal damage leading to varying degrees of neurological impairment. It causes episodes of neurological dysfunction lasting a few days or weeks (known as relapses), which tend to partially or completely resolve, especially in the early stages of the disease. With time, MS leads to progressive neurological impairment with or without relapses.1 The associated symptoms, disease progression and treatment response vary greatly,2 making the prognosis of individual patients uncertain. For this reason, the establishment of predictive and unified criteria to monitor treatment response might be useful to improve the clinical outcomes of MS treatments.

Since the launch onto the market of interferon beta (IFNβ) in 1993, attempts have been made to define suboptimal response criteria based on different predictive response factors, such as magnetic resonance imaging (MRI), disability progression, relapses or a combination thereof.3–8 In 2004, the Canadian Multiple Sclerosis Working Group developed a series of recommendations based on the three parameters outlined above.3 The “Rio Score” proposed in 2009,8 which laid the foundations for the evaluation of treatment response, has been modified and refined in other cohorts of patients.6,7,9 Since then, the paradigm of MS has changed due to the availability of new disease-modifying treatments (DMTs) and a better understanding of MS pathology.

However, there are no standard criteria regarding the definition of suboptimal response, or, therefore, for when a switch in DMT should be considered. This is likely due to multiple factors, including the absence of highly predictive, widely used criteria with reasonable sensitivity and sensibility, heterogeneity in patient follow-up between centres, and a mismatch between clinical trials and real-life clinical practice.5 As a result, a high percentage of MS patients do not present adequate control of their disease activity while receiving DMT. In this context, the establishment of treatment response criteria is critical. The aim of this study was to establish general consensus among MS neurologists on the variables that should be evaluated to monitor response to DMT.

Fig. 1 shows a schematic representation of the study methodology.

Figure 1.

Study methodology.

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Among the 790 MS neurologists who received the survey, 151 from 16 Spanish regions participated (participation rate 19%); 98 (65%) completed the survey, and 53 (35%) completed it partially. Most of the neurologists worked in tertiary-level hospitals (67%), saw ≥21 MS patients per month (65%) and conducted monographic visits of MS 1 or 2 days a week (56%) (Fig. 2).

Fig. 2.

Survey completion overview.

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Here, we describe the general agreement or disagreement obtained for each statement. Tables 1 and 2 show these results. Table A.1. shows the survey results for statements where general agreement or disagreement was not achieved.

The present study aimed to provide general consensus among MS neurologists on the monitoring of response to DMT as a way of optimising MS management. Establishing which assessments should be conducted to determine suboptimal treatment response is essential when reconsidering treatment modifications or switching between therapies. The therapeutic landscape for MS has significantly changed, with the approval of over ten new DMTs in the past decade alone; patients' clinical courses vary greatly; and patients do not all respond homogeneously to the same DMT. For these reasons, early identification of treatment failure is increasingly important, as it will make it possible to personalise treatment and to switch to a more beneficial DMT for each patient, ultimately improving the management of MS.

The results we obtained are highly representative of clinical practice throughout Spain, as MS neurologists from almost all regions of Spain participated in the study. MS neurologists agreed that MS patients should be evaluated 6–12 months after starting DMT to determine their therapeutic response. This frequency was previously recommended for the monitoring of clinical10 and radiological2 response after the start of DMT. MS neurologists also agreed that treatment response should be based on the evaluation of MRI scans, relapses and the progression of disability progression. Combining MRI and clinical activity has proven useful in previous approaches for identifying patients with suboptimal response.3,6–9,11,12 In patients treated with INFβ, MRI activity combined with relapses and/or increase of disability during the first year of treatment made it possible to detect patients at high risk of clinical activity and disease progression the next two years, while MRI or clinical activity alone did not (Rio score).8 A subsequent modification of the Rio score, which excluded the EDSS,7 accurately predicted treatment response,13 though the Rio score appeared slightly higher in high-risk patients.13 The assessment of the combination of MRI and clinical activity has also been recommended by the European treatment guidelines, despite the specific clinical activity to be measured not being specified.14

Additional agreement was achieved on ≥3 new/enlarged T2 lesions and ≥ 2 Gd-enhancing T1 lesions, separately, being sufficient to define suboptimal response. The T2 lesion cut-offs to detect therapeutic response vary among studies.5,7,9 The number of new/enlarged T2 and Gd-enhancing lesions agreed upon here is in line with the recommendations of the Canadian MS Working Group10 and with studies showing that ≥3 new/enlarged T2,11,15 and ≥ 2 Gd-enhancing lesions15 predicted short11 and long-term15 disability in INFβ-treated patients. Agreement was reached to perform reference brain MRI and follow-up MRI 3–6 and 12 months after the start of DMT, respectively, similarly to the recommendations in the European14 and MAGNIMS16 guidelines. It has been argued that the 3–6 month range for the reference MRI should be adapted depending on the pharmacodynamics of the DMT received.17 No assessment was considered necessary for patients with 1 relapse and ≥ 3 new T2 lesions, as this group of patients is considered non-responders. Additionally, no general consensus was observed about the use of spinal cord MRI when assessing therapeutic response.

In terms of clinical activity, it was agreed that disease progression should be considered when evaluating treatment response and that the EDSS and at least one other test should be conducted. Even though the EDSS is the most accepted tool for disability assessment, other measures such as the T25FW or the 9HPT are extensively used in the clinical setting. This is supported by evidence demonstrating that the addition of the T25FW and the 9HPT to the EDSS increased the identification of disability progression compared to each test alone.18 Additionally, using pooled clinical trial data, it has been shown that even though the EDSS alone predicted progression better than the T25FW and 9HPT together, when the latter are combined with Low Contrast Letter Acuity (LCLA) and the SDMT, they are more sensitive than the EDSS.19 This could be explained by the additive information from LCLA and the SDMT that is not captured by the other measurements, as suggested by the lack of correlation between the SDMT and EDSS.19 Accordingly, the use of the SDMT was agreed here to be a useful clinical tool for cognitive assessment, which should be performed annually for the evaluation of treatment response. The SDMT is widely considered a valid and reliable tool to measure cognitive changes in MS.20,21 It measures information processing speed, which is the most affected cognitive domain in MS.22 Since remote performance of the SDMT has proven similar validity and reliability as in-person testing,23 this format might be convenient, especially when patient mobility is limited.

Although patient-reported outcomes (PROs) to assess QoL have been underused in clinical practice, their implementation is expected to grow in the next years, as more MS-specific and validated PROs evidence increases.24 If resources were to become available, it was agreed that the evaluation of MS activity through serum neurofilaments, chitinase 3-like-protein-1, and OCT parameters should be periodically performed. Additionally, there was consensus for measuring BVL when monitoring treatment response. Including BVL with the modified Rio score improved prediction of disability progression compared to disease activity alone.25 However, the ≥0.4% threshold¸ previously proposed to be pathological in MS patients,26,27 was not agreed here to be indicative of lack of treatment response. Though adding BVL to the evaluation of treatment response is warranted, its implementation in routine clinical practice is still not straightforward. The main reasons might be the current lack of standardisation of acquisition protocols, technical expertise and resources to perform the post-processing of the images, together with other MRI scans or confounding factors of MS that hinder their interpretation.28 Overall, these fluid and structural biomarkers will need to be validated and the technical limitations overcome before their incorporation into the clinical setting.

MS neurologists agreed to escalate to a more effective DMT rather than to a DMT with a different mechanism of action, when relapses, MRI activity and disability progression or at least two of these measurements are detected. When only one of these outcomes is present, up to 40% of the MS neurologists agreed to switch to a more effective DMT, showing low tolerance to the presence of disease activity. Switching to a more effective DMT is supported by studies showing better outcomes with this strategy.29 In fact, it has been argued that early high-efficacy therapy results in better clinical outcomes. Ongoing randomised clinical trials (TREAT-MS and DELIVER-MS) will provide further evidence on which strategy is more adequate to prevent disease progression. Importantly, neurologists agreed that there are limitations to switching treatment in routine clinical practice, probably due to the accessibility to treatments. Despite these limitations, neurologists should aim to accurately identify individual responsiveness to treatment in a timely manner. The detection of treatment failure will allow them to consider, in dialogue with the patient and, based on the patient characteristics and preferences, the most effective, safe and convenient treatment switch for each patient, attaining a more personalised therapeutic approach.

Lastly, the present study highlighted the lack of a generally accepted definition of suboptimal treatment response in MS. Future efforts should be made to clarify the definition of suboptimal and optimal response. Regardless of if no evidence of disease activity or minimal evidence of disease activity are the goals to strive for, the incorporation of new measurements such as PROs, imaging and fluid biomarkers seems likely to occur along with advances in digital technology and artificial intelligence.

In conclusion, areas of agreement on the monitoring of DMT response were identified in all the categories. MS neurologists reached general agreement on which and when clinical and radiological measures should be performed and on changing the approach when a lack of response is detected. The results are expected to help neurologists to improve MS management. Future real-world studies will confirm whether this expectation is fulfilled.

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*All authors have contributed equally.

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This study was funded by Novartis Farmacéutica S.A. The sponsor did not have any role in the study design; in the collection, analysis, or interpretation of data; in the writing of the manuscript; or in the decision to submit the article for publication.

The study did not include human subjects and, therefore, no informed consent was required.

The study did not include human subjects and, therefore, this is not applicable.