Evolution of Disease Modifying Therapy Benefits and Risks: An Argument for De-escalation as a Treatment Paradigm for Patients With Multiple Sclerosis

Abstract

Background: Strategies for sequencing disease modifying therapies (DMTs) in multiple sclerosis (MS) patients include escalation, high efficacy early, induction, and de-escalation.

Objective: To provide a perspective on de-escalation, which aims to match the ratio of DMT benefit/risk in aging patients.

Methods: We reanalyzed data from a retrospective, real-world cohort of MS patients to model disease activity for oral (dimethyl fumarate and fingolimod) and higher efficacy infusible (natalizumab and rituximab) DMTs by age. For patients with relapsing MS, we conducted a controlled, stratified analysis examining odds of disease activity for oral vs. infusible DMTs in patients <45 or ≥45 years. We reviewed the literature to identify DMT risks and predictors of safe discontinuation.

Results: Younger patients had lower probability of disease activity on infusible vs. oral DMTs. There was no statistical difference after age 54.2 years. When dichotomized, patients <45 years on oral DMTs had greater odds of disease activity compared to patients on infusible DMTs, while among those ≥45 years, there was no difference. Literature review noted that adverse events increase with aging, notably infections in patients with higher disability and longer DMT duration. Additionally, we identified factors predictive of disease reactivation including age, clinical stability, and MRI activity.

Conclusion: In a real-world cohort of relapsing MS patients, high efficacy DMTs had less benefit with aging but were associated with increased risks. This cohort helps overcome some limitations of trials where older patients were excluded. To better balance benefits/risks, we propose a DMT de-escalation approach for aging MS patients.

Keywords: de-escalation; discontinuation; disease modifying therapy; escalation; high efficacy; infection; multiple sclerosis; relapse.

Figure 1

The probability of disease activity decreases over the lifetime of a patient with MS. (A) Probability of disease activity (clinical relapse, new T2 lesions, or enhancing lesions) observed in real-world study of 1,246 patients with MS with 95% confidence interval shown in dashed lines. (B) The probably of disease activity is higher in patients on oral (red; dimethyl fumarate and fingolimod) disease mofifying therapies (DMTs) than on infusible (blue; natalizumab and rituximab) DMTs. This probability is higher in younger patients and becomes non-significant by 54.2 years of age where the confidence intervals overlap. (C) Given the variable probability of disease activity, it is possible to observe that an escalation treatment approach under-treats early and over-treats as patients age resulting in possibly taking on higher risks but receiving little additional benefit from higher efficacy therapies. (D) High efficacy therapy early in the disease course matches the higher probability of disease activity early but can over-treat later in life. (E) Induction is often enough to sustain good efficacy early but some patients may breakthrough over time resulting in the need of retreatment or a maintenance therapy. (F) A de-escalation approach matches disease activity over a lifetime best, but will benefit from the use of better biomarkers to more rationally prompt changes in DMT. Shared decision making remains a crucial component of deciding on treatment approaches.