Escalation Approaches to Multiple Sclerosis Fail to Prevent Unfavorable Long-Term Outcomes


In a cohort study of 592 patients with MS, the findings were suggestive that real-world escalation approaches may be inadequate to prevent unfavorable long-term outcomes.

Dr Katharine Harding

Katharine Harding, PhD, of the Institute of Psychological Medicine and Clinical Neuroscience at the School of Medicine at Cardiff University

Katharine Harding, PhD

In a recent real-life setting study of escalation treatment compared to early intensive treatment, patients with multiple sclerosis (MS) who received high-efficacy treatments initially showed a smaller increase in disability scores after 5 years compared to those who first received moderate-efficacy disease-modifying therapy (DMT).1

According to lead author Katharine Harding, PhD, of the Institute of Psychological Medicine and Clinical Neuroscience at the School of Medicine at Cardiff University, and coauthors the findings are suggestive that escalation approaches to MS may be inadequate to prevent poor long-term outcomes in a real-life setting. The data additionally “support the need for a prospective clinical trial to compare disease-modifying therapy algorithms,” they wrote.

The trial ultimately found that those in the early intensive treatment (EIT) group (n = 104) had a mean 5-year change in Expanded Disability Status Scale (EDSS) score of 0.3 (standard deviation [SD], 1.5) compared to the moderate-efficacy DMT escalation (ESC) group (n = 488), which had an EDSS score of 1.2 (SD, 1.5), which remained significant after adjustment (95% CI, -1.38 to -0.32; P = .002). The median time to sustained accumulation of disability for the EIT group was 6.0 years (95% CI, 3.17 to 9.16) compared to 3.4 years (95% CI, 2.77 to 4.00) for the ESC group (P = .05).

Individuals who underwent EIT were more likely to receive alemtuzumab (n = 70; 67%) than natalizumab (n = 34; 33%), while those who received high-efficacy therapy as second-line treatment (part of an escalation algorithm) were more likely to receive natalizumab (n = 43; 74%) than alemtuzumab (n = 15; 26%). In the overall cohort, 61 patients received fingolimod, and in the sensitivity analysis, 2 were reclassified to the EIT group and 59 were classified as escalated from moderate- to high-efficacy DMT.

For those in the ESC group who escalated to a high-efficacy DMT as second-line treatment, the median time to sustained accumulation of disability was 3.3 years (95% CI, 1.8 to 5.6; comparison to EIT group, P = .08).

Although after Harding and colleagues adjusted for the relevant covariates, there was no significant difference in the hazard of sustained accumulation of disability between groups, in total, 60% of those who escalated to a high-efficacy DMT were observed to develop sustained accumulation of disability prior to the switch, while they were still receiving their initial, moderate-efficacy treatment. Of the 488 patients who began on a moderate-efficacy treatment, 11.9% (n = 58) went on to receive a high-efficacy DMT.

The switch to high-efficacy treatment was most often prompted by clinical disease activity (n = 52), while the almost all of the remaining cases were due to subclinical evidence of disease activity (n = 5) and a single case was prompted by clinician decision without evidence of clinically or radiologically measured disease activity during the year prior to escalation.

“In a real-life setting, long-term outcomes were more favorable following early intensive therapy [versus] first-line moderate-efficacy DMT,” Harding et al. detailed. “Contemporary surveillance strategies and escalation protocols may be insufficiently responsive. This finding is particularly relevant as patients in real-world practice are typically selected for an EIT approach to therapy on the basis of clinical and radiological features predictive of a poor outcome.”

The average time spent on any single disease-modifying drug was 2.0 years (95% CI, 1.8 to 2.4). The patients in the ESC group who escalated to a high-efficacy DMT took an average of 2.4 years (95% CI, 2.1 to 3.5) to escalate.

Harding and colleagues noted that the pretreatment annualized relapse rate (ARR) was higher in the EIT group (1.7; interquartile range [IQR], 0.9 to 2.8) than the ESC group (0.7; IQR, 0.4-1.3; P <.001), which was expected. Those who began on a moderate-efficacy DMT but escalated to a high-efficacy agent had a pretreatment ARR of 1.2 (IQR, 0.7 to 2.1) compared with 0.7 (IQR, 0.4 to 1.2) in those who continued with moderate-efficacy DMT (P <.001). ARR fell in all groups following the introduction of a DMT.

Following the use of DMT, the ARR in the ESC group was 0.16 (IQR, 0 to 0.5) compared to 0 (IQR, 0 to 0.3) in the EIT group (P = .02). Within the ESC group, the ARR following initial DMT was 0.9 (IQR, 0.7 to 1.5) in those who eventually escalated to high-efficacy treatment, while the ARR in that group following escalation was 0 (IQR, 0 to 0.2). In those who continued with moderate-efficacy agents, the ARR was 0.11 (IQR, 0-0.4; P = .01).

For adverse events (AEs), of those receiving alemtuzumab (n = 100), 87% developed infusion-related AEs and 47% developed autoimmunity (35 thyroid, 3 immune thrombocytopenic purpura, and 13 other), but no serious infections or treatment-related deaths occurred.

In patients receiving natalizumab, there were no serious AEs, no cases of progressive multifocal leukoencephalopathy, and no treatment-related deaths.

In patients receiving the moderate-efficacy DMTs, there were no treatment-related deaths but there were 7 serious AEs (rate, 1.4%), including 3 cases of necrotic skin reactions, 1 case of anaphylaxis while receiving injectable DMTs, and 3 severe infections while receiving fingolimod.

“The concept of escalation vs early intensive treatment strategies has arisen largely as a result of concerns over the complex safety profiles of the high-efficacy DMTs,” Harding and coauthors wrote. “Contemporary treatment algorithms often suggest reserving first-line high-efficacy treatments for individuals considered at highest risk of accumulating disability, usually those who meet an arbitrarily high level of clinical or radiological MS activity. For an escalation approach to be successful in the remaining cases, it is necessary that adequate procedure is in place to detect and respond to ‘failure’ of first-line moderate-efficacy DMTs without the individual accumulating permanent disability in the interim and that any delay does not diminish the efficacy of subsequent DMTs.”

Harding and others noted that the assumptions regarding the concept have not been tested in a randomized clinical trial, therefore the benefit of reserving high-efficacy interventions for those patients perceived to have the most active disease remains undecided. “We found that although patients were selected to receive EIT on the basis of poor prognostic factors including more active disease, it was this patient group that had better long-term outcomes,” they concluded.

"This data shows that in a very complex therapeutic landscape, routine data collected in NHS clinics has huge value in providing real-world evidence that can help to answer the questions that are important to patients,” Neil Robertson, MD, coauthor and a professor of neurology at the Helen Durham Centre for Neuroinflammatory Disease at the University Hospital of Wales, said in a statement.2

"In the meantime, there is work to be done in developing adequate procedures for treating patients using the escalation approach,” he added. “These need to detect where first-line treatments are failing to slow the progression of the disease and respond by moving patients to more effective therapies without people developing permanent disability."


1. Harding K, Williams O, Willis M, et al. Clinical outcomes of escalation vs early intensive disease-modifying therapy in patients with multiple sclerosis. JAMA Neurol. Published online February 18, 2019.



2. Early intensive therapy for multiple sclerosis leads to better long-term outcomes, despite being perceived as high risk [press release]. Cardiff, Wales: Cardiff University; Published February 20, 2019. Accessed February 21, 2019.

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