"Medical Journeys" is a set of clinical resources reviewed by doctors, meant for physicians and other healthcare professionals as well as the patients they serve. Each episode of this journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.
For many years, physicians have been treating multiple sclerosis (MS) with an "escalation" approach. This has typically meant starting patients on a mild-moderately effective disease-modifying therapy (DMT) until symptoms and/or imaging reveal disease breakthrough activity. At that point, treatment is often escalated to a higher-efficacy DMT.
Over time, however, this traditional treatment paradigm seems to be less entrenched as international treatment guidelines continue to vary on their recommendations for using specific DMTs. Data from a wide variety of clinical studies have shown that newer, higher-efficacy DMTs can have a positive long-term impact when started earlier in the disease course. As a result, many clinicians have shifted to a so-called "early aggressive" treatment approach in which they initially start patients on a higher-efficacy DMT.
Of the 20-plus available DMTs, the ones considered to be lower-efficacy therapies (LETs) are often referred to as first-line therapeutics. This group includes interferons, glatiramer (Copaxone), teriflunomide (Aubagio), and fumarates. The higher-efficacy therapy (HET) group includes sphingosine-1-phosphate modulators, natalizumab, anti-CD20 monoclonal antibodies, alemtuzumab (Lemtrada), and cladribine (Mavenclad), although some experts opinions on these may vary.
A 2021 by Scott D. Newsome, DO, and colleagues at Johns Hopkins School of Medicine in Baltimore, laid out some basic principles of MS DMTs that apply regardless of whether the clinician favors escalation or de-escalation treatment:
- Start treatment as soon as possible after initial symptom onset to give patients the best chance of minimizing long-term disability
- Maintain a low threshold for switching therapies when there is breakthrough disease activity (clinical relapses and/or new lesions on MRI) -- this may help prevent future disability
- If a patient has an inadequate (subtherapeutic) treatment response to a DMT, choose another DMT with a different mechanism of action
Rationale for Early Aggressive Treatment
As noted in a 2024 by Krzysztof Selmaj, MD, PhD, of the University of Warmia and Mazury in Poland, and colleagues, the irreversible pathology of MS is one of the most important justifications for early aggressive treatment. "Acute axonal loss is maximal in early MS and relates primarily to lesion activity. Demyelinated axons, surviving acute lesion formation, have limited potential for remyelination, particularly with increasing disease duration and age, and are susceptible to ongoing degeneration," the authors wrote. "Structural axonal changes cannot be repaired and are believed to, at least in part, underlie irreversible disability."
A 2022 by Léorah Freeman, MD, PhD, of the University of Texas at Austin, and colleagues cited the lack of prognostic ability to identify patients who do and do not respond to a given treatment as a rationale for considering an early aggressive approach: "Although a personalized approach to management is appropriate, at present it is not possible to predict the responder/non-responder status of individuals without having them try (and potentially fail) multiple MS drugs," the authors wrote. "Each drug failure can add cumulative neurologic disability, fueling the discussion about the most appropriate strategy to select a treatment for newly diagnosed patients."
Re-evaluating Safety in DMTs
Selmaj and co-authors noted that the real and perceived safety profile of DMTs has favored LETs: "For the last 25 years, it was widely accepted that LETs have a good safety profile. By contrast, a broad perception that HETs carry greater safety risks has limited their uptake. However, closer scrutiny of the safety of injectable drugs suggests that this is not entirely the case."
For example, interferon-beta is well known for its common flu-like side effects. Various clinical trials have also found that the agent is associated with increased rates of cytopenia, thyroid dysfunction, and possibly depression, which is already a concern in this patient population. Glatiramer may induce injection-site reactions, lipoatrophy, rash, skin necrosis, leukopenia, and thrombocytopenia.
Side effects from teriflunomide can include diarrhea, nausea, increased alanine transaminase levels, severe hepatotoxicity, and interstitial lung disease.
Reluctance to prescribe higher-efficacy DMTs early in the disease course may stem from the fact that early drugs in that class displayed a variety of concerning side effects. "Negative perceptions of the safety of HETs may have arisen from the high frequency of adverse events that occurred during therapy with the first agents, mitoxantrone (cardiomyopathy and promyelocytic leukemia) and natalizumab (progressive multifocal leukoencephalopathy) and then later with alemtuzumab (de novo autoimmune disease and thromboembolic events)," the authors said. "However, the results of recent long-term HET safety data have reversed this negative opinion considerably."
Treatment Strategies
According to Freeman and co-authors, the early aggressive treatment strategy is appropriate for people with relapsing-remitting MS at diagnosis, regardless of the patient's age or disability level. In addition to attempting to control clinically apparent inflammation, this strategy can "address the subclinical inflammatory activity that drives neuronal and brain volume loss (brain atrophy), preserve brain tissue and neurological reserve, and maximize long-term brain health," the team wrote. "This strategy is similar to early aggressive treatment approaches for other immune-mediated diseases, such as rheumatoid arthritis, which are known to improve long-term clinical outcomes."
The early HET approach encompasses both induction therapy, in which intermittent use aims to "reset" the immune system, as well as the more commonly used continuous treatment with high-efficacy DMTs. These DMTs include ofatumumab (Kesimpta), ocrelizumab (Ocrevus), ublituximab (Briumvi), natalizumab (Tysabri), alemtuzumab (Lemtrada), cladribine (Mavenclad), and rituximab (Mabthera; used off-label).
Ofatumumab is administered subcutaneously monthly (following three initial doses), without a need for dose adjustment based on individual patient characteristics. Ocrelizumab, ublituximab, and rituximab are administered intravenously every 6 months (following 2 initial doses), and natalizumab is administered intravenously every 4-6 weeks.
Comparative Trials
Retrospective and observational data can take the profession only so far, however. Many observers have noted the need for clinical trials that compare step-up versus step-down treatment approaches. By 2026, these answers should become clearer thanks to two pivotal trials currently underway.
The Traditional Versus Early Aggressive Therapy for MS () trial and the Determining the Effectiveness of Early Intensive Versus Escalation approaches for the treatment of Relapsing-remitting MS () trial aim to directly compare these treatment strategies and their impact on clinical and radiologic outcomes.
Newsome and co-authors include a comparing the study design and outcomes of DELIVER-MS and TREAT-MS (Newsome and co-author Ellen Mowry, MD, are the principal investigators of TREAT-MS).
In TREAT-MS, up to 900 participants will be stratified for higher versus lower risk for long-term disability, and then receive 1:1 randomization within each disability risk group. The primary outcome is the time to sustained disability progression using blinded Expanded Disability Status Scale-Plus, with a timeframe of up to 63 months. TREAT-MS is expected to be completed in 2025.
In DELIVER-MS, investigators are using a trial design that can enroll up to 800 participants. Half of the participants will be randomized 1:1 to either traditional or early aggressive treatment. The other cohort will be reserved for participants who are unable or unwilling to be randomized. The primary outcome will be normalized whole brain volume loss using MRI from baseline to month 36. The expectation is that the trial data will be reported in 2026.
Regardless of what TREAT-MS and DELIVER-MS eventually find, or what new DMTs enter clinical practice, shared decision-making should remain the centerpiece of clinical practice, noted Freeman and co-authors. "Based on the need for efficacious treatment in the early stages of MS disease, we believe HETs are appropriate for most patients with relapsing MS as a first-line treatment option. However, a shared decision-making approach should occur between the patient and their care teams, including comprehensive discussions on available treatment options as well as the benefits and risks of early HET use, to ensure that an informed decision is made as a team on the appropriate treatment."
Read previous installments in this series:
Part 1: Early Diagnosis Can Mean Better Outcomes in Multiple Sclerosis
Part 2: How Does Multiple Sclerosis Start?
Part 3: The Deep and Multidimensional Connection Between Multiple Sclerosis and Depression