Evolving concepts in the treatment of relapsing multiple sclerosis

doi:10.1016/S0140-6736(16)32388-1

The Lancet

Volume 389, Issue 10076, 1–7 April 2017, Pages 1347-1356

https://doi.org/10.1016/S0140-6736(16)32388-1 Get rights and content

Summary

In the past 20 years the treatment scenario of multiple sclerosis has radically changed. The increasing availability of effective disease-modifying therapies has shifted the aim of therapeutic interventions from a reduction in relapses and disability accrual, to the absence of any sign of clinical or MRI activity. The choice for therapy is increasingly complex and should be driven by an appropriate knowledge of the mechanisms of action of the different drugs and of their risk-benefit profile. Because the relapsing phase of the disease is characterised by inflammation, treatment should be started as early as possible and aim to re-establish the normal complex interactions in the immune system. Before starting a treatment, neurologists should carefully consider the state of the disease, its prognostic factors and comorbidities, the patient's response to previous treatments, and whether the patient is likely to accept treatment-related risks in order to maximise benefits and minimise risks. Early detection of suboptimum responders, thanks to accurate clinical monitoring, will allow clinicians to redesign treatment strategies where necessary.

Introduction

More than 20 years after approval of the first drug to treat relapsing-remitting multiple sclerosis, the range of treatments for multiple sclerosis has incredibly expanded. The new classification of multiple sclerosis phenotypes, with separation of the two major phenotypes (the relapsing and the progressive course) and further subcategorisation according to the presence or absence of disease activity, has made a valid contribution to a better definition of multiple sclerosis treatment.¹ This classification recognises the pathogenic differences of the two main courses, with the obvious treatment implications; in the meantime, criteria such as disease activity guides treatment decisions. In this, the second in a Series of three papers about multiple sclerosis, we focus on the two key concepts that should guide our therapeutic algorithm: a tailored approach and early treatment.

Section snippets

The need to personalise disease-modifying therapies

So far, more than 10 disease-modifying drugs have been approved for relapsing-remitting multiple sclerosis. An appropriate knowledge of drug mechanisms of action and an accurate evaluation of the benefits and risks of the different treatments has become crucial to making the correct therapeutic decisions.² Evidence from clinical trials and daily clinical practice has shown that only some patients respond satisfactorily to a given treatment, and the one-size-fits all approach is not the best

Early treatment

Many converging lines of evidence support the great importance of early treatment (figure 1). A natural history study confirmed that multiple sclerosis is a serious disease; approximately 80% of patients develop severe disability⁵⁴ and life expectancy is reduced by 10 years.⁵⁵ The main determinant of irreversible disability is axonal damage. Pathological studies have shown a variable degree of axonal transection in acute lesions.⁵⁶ Both MRI57, 58 and optical coherence tomography studies59, 60

Therapeutic strategies

Two treatment strategies are usually used in patients with multiple sclerosis: the induction strategy and escalating strategy.⁷⁷ The decision is based on the prognostic profile of each single patient. The concept of induction means performing a strong immunointervention as soon as the diagnosis is certain or even in patients with a first episode suggestive of multiple sclerosis if there are negative prognostic factors and a typical presentation. The rationale of escalating therapy is to start

Conclusions and future perspectives

In the past 20 years, treatment for relapsing multiple sclerosis has completely changed, with new interesting perspectives opening up. Even considering the methodological issues that could undermine their quality, randomised controlled trials and post-marketing studies have consistently shown that disease-modifying therapies can influence long-term disease evolution and reduce the frequency of episodes, disability accrual, and accumulation of irreversible nerve damage.

Early treatment with an

Search strategy and selection criteria

We searched Medline using the search terms “DMTs”, “treatment algorithm”, “response to treatment”, and “early treatment” in combination with the term “multiple sclerosis”. We selected articles published from Jan 1, 1993, to July 30, 2016. We largely selected publications in the past 5–6 years, but did not exclude commonly referenced and highly regarded older publications. We also looked for the reference lists of articles identified by this research strategy and selected those considered more

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Cited by (244)

Association of oral disease-modifying agents and their adherence trajectories with annual relapses in multiple sclerosis
2024, Multiple Sclerosis and Related Disorders
Real-world effectiveness can vary across oral disease-modifying agents (DMAs) and their adherence trajectories in patients with multiple sclerosis (MS). However, previous studies have not considered longitudinal adherence patterns while evaluating oral DMAs.
This study aimed to evaluate the association of oral DMAs and their adherence trajectories with annualized relapse rate (ARR) in patients with MS.
This retrospective observational cohort study based on the 2015–2019 MarketScan Commercial Claims and Encounters Database involved continuous enrolled adults (18–64 years) with ≥1 MS diagnosis (ICD-9/10-CM:340/G35) and ≥ 1 oral DMA prescription. Patients were grouped into incident fingolimod (FIN), teriflunomide (TER), and dimethyl fumarate (DMF) users based on the index DMA with a one-year washout period. Annual DMA adherence trajectories based on the monthly Proportion of Days Covered (PDC) one year after treatment initiation were identified using Group-Based Trajectory Modeling (GBTM). The validated claims-based ARR was evaluated during the one-year follow-up period using generalized boosted model-based inverse probability treatment weights with negative binomial regression model.
The study cohort consisted of 994 MS patients who initiated with FIN (23.0%), TER (22.3%), and DMF (54.7%) during the study period. GBTM grouped eligible patients into three adherence trajectories: complete adherers (59.2%), slow decliners (23.8%), and rapid decliners (17.0%). The proportion of complete adherers varied across the oral DMAs (FIN: 67.1%, TER: 55.4%, and DMF: 57.4%). The negative binomial regression modeling revealed that, while there was no difference in ARR across the three DMAs, rapid decliners (adjusted incidence rate ratio[aIRR]: 1.6, 95% CI: 1.1–2.4) had a higher rate of relapses compared to completely adherent patients. The type of oral DMAs did not moderate the relationship between ARR and the adherence trajectory groups.
Adherence trajectories classified as rapid decliners were associated with a higher ARR than complete adherers after adjusting for their type of oral DMAs. Longitudinal medication adherence patterns are critical in reducing relapse rates in MS.
Burden of treatment and quality of life in relapsing remitting multiple sclerosis patients under early high efficacy therapy in Argentina: Data from the Argentinean registry
2024, Multiple Sclerosis and Related Disorders
The objective of this study was to describe and compare the burden of treatment (BOT) and the quality of life (QoL) in early high efficacy therapy (HET) vs. escalation therapy in relapsing remitting multiple sclerosis (RRMS) patients included in RelevarEM, the Argentinean registry of MS (RelevarEM, NCT 03,375,177).
cross sectional study conducted between September and December 2022. Participating patients were adults, RRMS patients who initiated (during the last three years) their treatment with a HET (natalizumab, ocrelizumab, alemtuzumab, cladribine) or with escalation treatment (beta interferon, glatiramer acetate, teriflunomide, dimethyl fumarate or fingolimod). Clinical and demographic aspect were collected. QoL and BOT was measured with the validated to Spanish MusiQol and BOT questionnaire. Propensity score (PS)-based nearest-neighbor matching was applied to homogenize groups. Comparisons were be done using a linear regression analysis model stratified by matched pairs, with BOT and QoL assessments as main outcomes.
269 patients were included in the analysis, mean age 33.7 ± 5.7 years, 193 (71.7 %) were female. A total of 136 patients were on early HET while 133 were on escalation therapy. In the entire group the mean total BOT score (±SD) was 48.5 ± 15.3 while in the group of patients receiving early HET we observed that the mean BOT score (±SD) was 43.5 ± 12.2 vs. 54.3 ± 13.3 in escalation treatment (p < 0.0001). Regarding the score QoL (±SD), in the entire sample we observed a global score of 77.4 ± 11.2. When we stratified groups, in HET (±SD) it was 81.3 ± 14 vs. 74.1 ± 18.3 in escalation therapy (p = 0.0003).
in this multicenter study that included 269 patients from Argentina we observed in early HET a significantly lower BOT and higher QoL than patients receiving escalation therapy.
Defining a standard set of health outcomes for patients with relapsing-remitting multiple sclerosis
2024, Multiple Sclerosis and Related Disorders
Standardizing health outcomes is challenging in clinical management, but it also holds the potential for creating a healthcare system that is both more effective and efficient. The aim of the present study is to define a standardized set of health outcomes for managing Relapsing-Remitting Multiple Sclerosis (RRMS).
The project was led and coordinated by a multidisciplinary scientific committee (SC), which included a literature review, a patient-focused group, three nominal group meetings, and two SC meetings.
36 outcome variables were included in the standard set: 24 clinical (including weight, smoking habit, comorbidities, disability, mobility, diagnosis of secondary progressive multiple sclerosis, relapsed-related variables, radiological variables, cognitive status and disease-related symptoms), nine treatment-related (pharmacological and non-pharmacological information), and 3 related to the impact of RRMS on the patient's life (quality of life, pregnancy desire, work-related difficulties). In addition, experts also agreed to collect 10 case-mix variables that may affect but cannot be controlled as part of the management of the condition: 4 sociodemographic (age, sex, race, and employment status) and 6 clinical (height, date of diagnosis and first episode, serological status, early symptoms, and number of relapses pre-diagnosis).
The information provided through the present standard set of outcome variables can improve the management of RRMS and promote patient-centred quality care.
Evaluation of the use of high-efficacy treatments (HETs) in patients with relapsing-remitting multiple sclerosis in Argentina
2023, Multiple Sclerosis and Related Disorders
Disease-modifying therapies (DMTs) in multiple sclerosis (MS) can be classified according to the efficacy in which they prevent inflammatory activity. To date, there are limited data regarding the use of high-efficacy treatments (HETs) in Latin America (LATAM). We aimed to analyze the use of HETs in Argentina, focusing on the clinical and sociodemographic characteristics of the patients who use these treatments and the changes in the trend of use over the years.
A retrospective cohort study was done using the Argentina MS patient registry, RelevarEM. Patients diagnosed with relapsing-remitting MS (RRMS) according to validated diagnostic criteria and under treatment with natalizumab, alemtuzumab, cladribine, rituximab or ocrelizumab were included.
Out of 2450 RRMS patients under a DMT, 462 (19%) were on HETs. One third of those patients (35%) received HETs as the first treatment. The most frequent reason for switching to HETs was treatment failure to previous DMT (77%). The time from MS diagnosis to the first HET in treatment-naive patients was less than one year (IQR: 0–1 year) and in treatment-experienced patients it was 5 years (IQR: 3–9 years). Between 2015 and 2017 (P1), 729 patients included in RelevarEM started a new treatment, of which 85 (11.65%) were HETs. Between 2018 and 2020 (P2), 961 patients included in RelevarEM started a new treatment, of which 284 (29.55%) were HETs. When comparing P2 with P1, a significant increase in the use of HETs was observed (p < 0.01). The most frequently used HETs were alemtuzumab (50.59%) in P1, and cladribine (45.20%) in P2.
The demographic and clinical characteristics of patients under HET in Argentina were identified. Based on a real-world setting, we found a significant trend towards and a rapid increase in the use of HETs in clinical practice in patients with RRMS.
Sphingosine 1-phosphate signaling during infection and immunity
2023, Progress in Lipid Research
Sphingolipids are essential components of all eukaryotic membranes. The bioactive sphingolipid molecule, Sphingosine 1-Phosphate (S1P), regulates various important biological functions. This review aims to provide a comprehensive overview of the role of S1P signaling pathway in various immune cell functions under different pathophysiological conditions including bacterial and viral infections, autoimmune disorders, inflammation, and cancer. We covered the aspects of S1P pathways in NOD/TLR pathways, bacterial and viral infections, autoimmune disorders, and tumor immunology. This implies that targeting S1P signaling can be used as a strategy to block these pathologies. Our current understanding of targeting various components of S1P signaling for therapeutic purposes and the present status of S1P pathway inhibitors or modulators in disease conditions where the host immune system plays a pivotal role is the primary focus of this review.
Assessing treatment switch among patients with multiple sclerosis: A machine learning approach
2023, Exploratory Research in Clinical and Social Pharmacy
Patients with multiple sclerosis (MS) frequently switch their Disease-Modifying Agents (DMA) for effectiveness and safety concerns. This study aimed to develop and compare the random forest (RF) machine learning (ML) model with the logistic regression (LR) model for predicting DMA switching among MS patients.
This retrospective longitudinal study used the TriNetX data from a federated electronic medical records (EMR) network. Between September 2010 and May 2017, adults (aged ≥18) MS patients with ≥1 DMA prescription were identified, and the earliest DMA date was assigned as the index date. Patients prescribed any DMAs different from their index DMAs were considered as treatment switch. . The RF and LR models were built with 72 baseline characteristics and trained with 70% of the randomly split data after up-sampling. Area Under the Curves (AUC), accuracy, recall, G-measure, and F-1 score were used to evaluate the model performance.
In this study, 7258 MS patients with ≥1 DMA were identified. Within two years, 16% of MS patients switched to a different DMA. The RF model obtained significantly better discrimination than the LR model (AUC = 0.65 vs. 0.63, p < 0.0001); however, the RF model had a similar predictive performance to the LR model with respect to F- and G-measures (RF: 72% and 73% vs. LR: 72% and 73%, respectively). The most influential features identified from the RF model were age, type of index medication, and year of index.
Compared to the LR model, RF performed better in predicting DMA switch in MS patients based on AUC measures; however, judged by F- and G-measures, the RF model performed similarly to LR. Further research is needed to understand the role of ML techniques in predicting treatment outcomes for the decision-making process to achieve optimal treatment goals.

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SeriesEvolving concepts in the treatment of relapsing multiple sclerosis

Summary

Introduction

Section snippets

The need to personalise disease-modifying therapies

Early treatment

Therapeutic strategies

Conclusions and future perspectives

Search strategy and selection criteria

Lancet Neurol

Lancet

Lancet Neurol

Lancet

Lancet

Lancet Neurol

Lancet Neurol

Clin Immunol

Clin Ther

Mult Scler Relat Disord

Mult Scler Relat Disord

Autoimmun Rev

Lancet

Lancet Neurol

Lancet Neurol

Lancet

Lancet

Lancet Neurol

Lancet Neurol

Mult Scler Relat Disord

Lancet Neurol

Mult Scler Relat Disord

J Neurol Sci

Lancet

Clin Ther

Defining the clinical course of multiple sclerosis: The 2013 revisions

Neurology

New management algorithms in multiple sclerosis

Curr Opin Neurol

Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG)

Ann Neurol

Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis

Lancet

Interferon beta-1b is effective in relapsing-remitting multiple-sclerosis – clinical-results of a multicenter, randomized, double-blind, placebo-controlled trial

Neurology

European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging-measured disease activity and burden in patients with relapsing multiple sclerosis

Ann Neurol

A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis

N Engl J Med

A Placebo-Controlled Trial of Oral Fingolimod in Relapsing Multiple Sclerosis

N Engl J Med

Randomized trial of oral teriflunomide for relapsing multiple sclerosis

N Engl J Med

Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis

N Engl J Med

Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis

N Engl J Med

Gene expression analysis of interferon-β treatment in multiple sclerosis

Mult Scler

Mechanisms of action of glatiramer acetate in multiple sclerosis

Neurology

Sustained clinical benefits of glatiramer acetate in relapsing multiple sclerosis patients observed for 6 years. Copolymer 1 Multiple Sclerosis Study Group

Mult Scler

Randomized study combining interferon and glatiramer acetate in multiple sclerosis

Ann Neurol

Neutralizing antibodies hamper IFN beta bioactivity and treatment effect on MRI in patients with MS

Neurology

Teriflunomide versus subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis: a randomised, controlled phase 3 trial

Mult Scler

Management of multiple sclerosis and the integration of related specialty pharmacy programs within health systems

Am J Health Syst Pharm

BG-12 in multiple sclerosis

Semin Neurol

Dimethyl fumarate in multiple sclerosis: latest developments, evidence and place in therapy

Ther Adv Chronic Dis

Mechanisms of fingolimod's efficacy and adverse effects in multiple sclerosis

Ann Neurol

Clinical immunology of the sphingosine 1-phosphate receptor modulator fingolimod (FTY720) in multiple sclerosis

Neurology

Series
Evolving concepts in the treatment of relapsing multiple sclerosis