Escalation or high-efficacy disease-modifying therapies in multiple sclerosis

Document Type : Letter to Editor


Multiple Sclerosis (MS) Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.


Main Subjects

Dear Editor,


Considering safety and future disability, which approach (high-efficacy disease-modifying therapy OR escalation) is preferable in multiple sclerosis (MS) patients?

Search strategy

The search was performed in PubMed and Cochrane databases using the keywords “multiple sclerosis” AND “escalation” OR “early intense therapy” OR “high efficacy therapy” OR “high efficacy disease-modifying therapy”.

Cochrane Results: not matched

Search outcome

Forty articles were found. Title and abstracts of all articles were evaluated. 14 relevant studies were found: 3 cohorts, 6 reviews, 3 cross-sectional retrospectives, 1 clinical trial, and 1 editorial. Three recent and most relevant articles were selected.


The treatment strategy for MS is a highly controversial debate. Disease-modifying therapies for MS are divided into escalation therapies and high-efficacy therapies. Escalating treatment means starting with the safest disease-modifying therapies with moderate effect. High-efficacy therapies mean starting with a strong immune intervention.

The majority of studies agree on this issue that the advantage of the escalation scheme is to allow many patients to have satisfying control of the disease while receiving relatively safe drugs and never escalating to more aggressive therapy (Table 1). But the disadvantage is exposing some patients to the risk of losing precious years spent receiving a treatment that was not potent enough and potentially leading to sustained accumulation of disability. The advantage of high-efficacy disease-modifying therapies is to facilitate an earlier achievement of ‘‘no evidence of disease activity’’, and the disadvantage is the risk to expose some patients needlessly to serious side effects.

Clinical bottom line

The current challenge in therapeutic strategy is to identify the most effective drug and strategy during a specific phase of the disease of every single patient. Sex, age, and presenting symptoms might predict increased disease severity in MS patients. With present markers, such as volumetric MRI and emerging markets such as serum neurofilament light chain, early and accurate prognostication in individual patients will become possible. New MRI techniques (brain and spinal cord imaging) should help us to identify those MS patients, especially individuals without any real disability, who are more at risk of developing destructive CNS lesions with or without first-line therapy and who are therefore more eligible for an early and more aggressive treatment strategy (6).

The higher costs of high-efficacy therapies can present challenges, particularly for patients without comprehensive insurance coverage or those residing in regions with limited access to healthcare resources. Escalation therapies, on the other hand, may be more cost-effective initially, but they might not provide the same level of disease control as high-

Table 1. Results of the included studies

Harding et al. (1)


A total of 592 MS patients (104 received early intense therapy and 488 received escalation therapy)

Study type

A population-based cohort of patients with MS


Five-year change in Expanded Disability Status Scale (EDSS) score, and time to sustained accumulation of disability (SAD)

Key results

Those who received high-efficacy treatment initially had a smaller increase in EDSS score at 5 years vs those who first received moderate-efficacy disease-modifying therapy. There was no difference in hazard of SAD between the groups

Study weakness

A lack of uniformly acquired imaging or adverse event data compared with clinical trials

Prosperini et al. (2)


3851 patients in the escalation group and 132 in the induction group who started treatment from 1998 to 2009, successfully matched 150 MS patients (75 early intense therapy and 75 escalation therapy) were included

Study type

Retrospective, independent, multicenter, post-marketing study


Serious adverse events, risk of reaching the disability milestone

Key results

Lower proportion of patients reached the milestone of EDSS 6 at 10 years, in patients with poor prognostic factors, induction was more effective than escalation in reducing the risk of reaching the disability milestone, albeit with a worse safety profile

Study weakness

Retrospective design, small sample size (especially for induction group), and comparison of patients in different treatment eras (MTX and CYC are no longer prescribed given the increased availability of newer drugs)

Due Buron et al. (3)


388 MS patients, 194 starting initial therapy with high-efficacy disease-modifying therapies matched to 194 patients starting medium-efficacy disease-modifying therapies.

Study type

A cohort study


The probabilities of a 6-month confirmed EDSS score worsening, probability of a first relapse

Key results

Lower probability of 6-month confirmed EDSS score worsening and lower probability of a first relapse in patients starting a medium-efficacy disease-modifying therapies as first

Study weakness

They were not compared the characteristics and severity of adverse events between the study groups.

Simonsen et al. (4)


694 patients diagnosed with MS who had been treated with either moderate efficacy disease modifying therapies or high efficacy DMTs for at least 12 months

Study type

A cohort study


the impact of initial treatment choice in achieving no evidence of disease activity (NEDA) at year 1 and 2.

Key results

Patients treated with high-efficacy disease modifying therapies have a notably higher likelihood of achieving NEDA at year 1 and 2 compared to those on moderate efficacy therapies, and the initial treatment selection plays a crucial role

Study weakness

Some patients were excluded from the study due to missing or incomplete information

Rojas et al. (5)


patients with relapsing-remitting multiple sclerosis in Argentina

Study type

retrospective multicenter cohort study


confirmed disability progression (Expanded Disability Status Scale [EDSS] increase); the proportion of patients and time to: EDSS 6; new relapses; new T2–magnetic resonance imaging (MRI) lesions; no evidence of disease activity; and specific adverse events

Key results

study shows that early high-efficacy therapies prevent disease progression, relapses, and new MRI lesions and demonstrated no increased risk of specific adverse events when compared with Escalation therapy

Study weakness

the study did not include a direct comparison of the cost-effectiveness of the two treatment approaches

efficacy options (5).

High-efficacy disease-modifying therapies (DMTs) in the context of MS can provide potent control over the disease, but they are also accompanied by potential adverse effects (7). These may encompass immunosuppression, reactions during infusion or injection, potential harm to the liver, cardiac complications, an elevated risk of developing certain cancers, blood-related disorders, headaches, flu-like symptoms, gastrointestinal disturbances, and alterations in mood. Patients considering the use of high-efficacy DMTs should be well-informed about these potential side effects and engage in comprehensive discussions with their healthcare providers to carefully assess the risks and benefits of these treatment options tailored to their individual MS management plan (8). Regular monitoring and open communication with healthcare providers are fundamental to effectively manage any possible side effects and maximize the benefits of these therapies (1).

Considering lifestyle modifications, especially exercise and diet, alongside disease-modifying therapies is crucial in managing MS. Lifestyle factors can significantly impact the disease's progression and should be a part of the overall treatment strategy. Regular exercise offers numerous benefits for individuals with MS, including improved muscle strength, balance, mobility, reduced fatigue, and enhanced mood and well-being (9). A well-balanced diet, rich in nutrients, antioxidants, and omega-3 fatty acids, can help reduce inflammation and support brain health in MS patients. Including information about lifestyle modifications in treatment discussions would lead to a more comprehensive approach to MS management, empowering patients to actively participate in their care and enhance their overall health and quality of life (10).




We do not have any financial support for this study.

Conflict of interest

The authors declare no conflict of interest regarding the publication of this paper.

Ethical approval

No need

Consent for publication

This manuscript has been approved for publication by all authors.

  1. References

    1. Harding K, Williams O, Willis M, Hrastelj J, Rimmer A, Joseph F, et al. Clinical outcomes of escalation vs early intensive disease-modifying therapy in patients with multiple sclerosis. JAMA neurology. 2019;76(5):536-41.
    2. Prosperini L, Mancinelli CR, Solaro CM, Nociti V, Haggiag S, Cordioli C, et al. Induction versus escalation in multiple sclerosis: a 10-year real world study. Neurotherapeutics. 2020;17:994-1004.
    3. Buron MD, Chalmer TA, Sellebjerg F, Barzinji I, Christensen JR, Christensen MK, et al. Initial high-efficacy disease-modifying therapy in multiple sclerosis: a nationwide cohort study. Neurology. 2020;95(8):e1041-e51.
    4. Simonsen CS, Flemmen HØ, Broch L, Brunborg C, Berg-Hansen P, Moen SM, et al. Early high efficacy treatment in multiple sclerosis is the best predictor of future disease activity over 1 and 2 years in a Norwegian population-based registry. Frontiers in Neurology. 2021;12:693017.
    5. Rojas JI, Patrucco L, Alonso R, Garcea O, Deri N, Contentti EC, et al. Effectiveness and safety of early high-efficacy versus escalation therapy in relapsing-remitting multiple sclerosis in Argentina. Clinical Neuropharmacology. 2022;45(3):45-51.
    6. Fenu G, Lorefice L, Frau F, Coghe G, Marrosu M, Cocco E. Induction and escalation therapies in multiple sclerosis. Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Inflammatory and Anti-Allergy Agents). 2015;14(1):26-34.
    7. Freeman L, Longbrake EE, Coyle PK, Hendin B, Vollmer T. High-Efficacy Therapies for Treatment-Naïve Individuals with Relapsing–Remitting Multiple Sclerosis. CNS drugs. 2022:1-15.
    8. Filippi M, Amato MP, Centonze D, Gallo P, Gasperini C, Inglese M, et al. Early use of high-efficacy disease‑modifying therapies makes the difference in people with multiple sclerosis: an expert opinion. Journal of Neurology. 2022;269(10):5382-94.
    9. Peel C. Disease-modifying lifestyle in multiple sclerosis: evidence, challenges, and the importance of engaged, informed patients. British Journal of Neuroscience Nursing. 2023;19(Sup3):S11-S6.
    10. Antonovich N. Discontinuing Disease-Modifying Therapies in Nonactive Secondary Progressive MS: Review of the Evidence. Federal Practitioner. 2023;40.
Volume 2, Issue 2
July 2023
Pages 106-108
  • Receive Date: 27 July 2023
  • Revise Date: 06 August 2023
  • Accept Date: 08 August 2023