Comparing Multiple Sclerosis Treatments: Which Therapies Work Best Over 5 Years?

Table of Contents

• Why This Research Matters
• How the Research Was Conducted
• Detailed Treatment Comparison Results
• What This Means for Patients
• What the Study Couldn't Prove
• Actionable Advice for Patients
• Source Information

Why This Research Matters

Multiple sclerosis (MS) is a chronic neurological condition where the immune system attacks the protective covering of nerve fibers. Disease-modifying therapies (DMTs) are medications that can reduce relapses (flare-ups of symptoms), slow disability progression, and delay the transition to more advanced stages of MS. With many treatment options available, patients and neurologists need clear evidence about which therapies work best over the long term.

Randomized clinical trials typically compare one treatment against placebo, but they rarely compare multiple treatments directly against each other. This creates a significant gap in our knowledge about which therapies are most effective for different patients. This international study aimed to fill that gap by analyzing real-world data from thousands of patients followed for up to five years.

The research team used advanced statistical methods to emulate what a multi-treatment randomized trial would show if it were practical to conduct one. They compared six commonly used therapies: natalizumab (Tysabri), fingolimod (Gilenya), dimethyl fumarate (Tecfidera), teriflunomide (Aubagio), interferon beta (various brands), and glatiramer acetate (Copaxone), along with no treatment.

How the Research Was Conducted

Researchers analyzed data from 23,236 patients with relapsing-remitting MS or clinically isolated syndrome (an early form of MS) from 74 medical centers across 35 countries. The data came from the MSBase registry, an international database that tracks MS patients over time. Patients were followed from their first clinic visit with disability data recorded, with an average follow-up of 2.8 years.

The study used sophisticated statistical techniques called marginal structural models to compare treatments while accounting for differences between patient groups. This approach helped balance the comparison groups on important factors like:

• Age, sex, and pregnancy status
• Disease duration and disability level
• Previous treatment history
• Recent relapse activity
• MRI findings (when available)

Patients were analyzed from their first recorded treatment episode and followed until they switched treatments, discontinued, or reached the end of the study period. The researchers examined three main outcomes: relapse frequency, confirmed disability worsening (lasting at least 12 months), and confirmed disability improvement (also lasting at least 12 months).

The statistical methods created weighted comparisons that essentially asked: "What would happen if the same group of patients received different treatments?" This allowed for more fair comparisons between treatments that are typically prescribed to different types of patients in real-world practice.

Detailed Treatment Comparison Results

The study produced two types of comparisons: average treatment effects (ATE) that show how treatments would perform across all patients, and average treatment effects among the treated (ATT) that show how treatments compare in the specific patient groups that typically receive them.

Relapse Reduction

Compared to glatiramer acetate (used as the reference treatment), several therapies showed superior effectiveness in reducing relapses:

• Natalizumab: 56% reduction in relapse risk (HR=0.44, 95% CI=0.40 to 0.50)
• Fingolimod: 40% reduction in relapse risk (HR=0.60, 95% CI=0.54 to 0.66)
• Dimethyl fumarate: 22% reduction in relapse risk (HR=0.78, 95% CI=0.66 to 0.92)
• Teriflunomide: 11% reduction that was not statistically significant (HR=0.89, 95% CI=0.75 to 1.06)
• Interferon beta: 5% reduction that was borderline significant (HR=0.95, 95% CI=0.89 to 1.00)
• No treatment: 35% increased relapse risk (HR=1.35, 95% CI=1.27 to 1.44)

Disability Worsening

For preventing confirmed disability worsening (lasting at least 12 months):

• Natalizumab: 57% reduction in disability worsening risk (HR=0.43, 95% CI=0.32 to 0.56)
• Fingolimod: 15% reduction that was not statistically significant (HR=0.85, 95% CI=0.67 to 1.06)
• Dimethyl fumarate: 14% reduction that was not statistically significant (HR=0.86, 95% CI=0.51 to 1.47)
• Teriflunomide: 44% reduction (HR=0.56, 95% CI=0.31 to 0.99)
• Interferon beta: 8% increased risk that was not significant (HR=1.08, 95% CI=0.96 to 1.23)
• No treatment: 4% increased risk that was not significant (HR=1.04, 95% CI=0.89 to 1.21)

Disability Improvement

For promoting confirmed disability improvement (lasting at least 12 months):

• Natalizumab: 32% increased chance of improvement (HR=1.32, 95% CI=1.08 to 1.60)
• Fingolimod: 18% increased chance that was not significant (HR=1.18, 95% CI=0.96 to 1.46)
• Dimethyl fumarate: 15% increased chance that was not significant (HR=1.15, 95% CI=0.82 to 1.60)
• Teriflunomide: 30% reduced chance that was not significant (HR=0.70, 95% CI=0.44 to 1.11)
• Interferon beta: 3% increased chance that was not significant (HR=1.03, 95% CI=0.91 to 1.18)
• No treatment: 9% reduced chance that was not significant (HR=0.91, 95% CI=0.78 to 1.05)

The pairwise comparisons (ATT models) confirmed that natalizumab and fingolimod consistently showed superior effects compared to other therapies for both relapse reduction and disability outcomes. These results remained consistent even when accounting for MRI findings and when using different reference treatments for comparison.

What This Means for Patients

This study provides strong evidence that not all MS treatments are equally effective. The higher-efficacy therapies, particularly natalizumab and fingolimod, showed significantly better outcomes for reducing relapses and preventing disability progression compared to moderate-efficacy therapies.

For patients with active relapsing-remitting MS, these findings suggest that starting with or switching to higher-efficacy treatments may provide better long-term protection against disease activity. The 56% reduction in relapse risk with natalizumab and 40% reduction with fingolimod represent substantial clinical benefits that could translate to fewer hospitalizations, less time off work, and better quality of life.

The disability outcomes are particularly important because they reflect long-term progression that significantly impacts daily functioning. Natalizumab's 57% reduction in disability worsening risk and 32% increased chance of disability improvement suggest it may not only slow disease progression but potentially allow for some recovery of function.

These results support the concept of "treatment escalation" - starting with higher-efficacy therapies for patients with more active disease, rather than following a step-by-step approach that begins with moderate-efficacy treatments. This approach may help prevent irreversible disability accumulation over time.

What the Study Couldn't Prove

While this study provides valuable real-world evidence, it has several limitations that patients should understand:

• Not a randomized trial: Despite advanced statistical methods, this remains an observational study, which means treatment decisions were made by doctors and patients rather than random assignment
• Treatment selection bias: Higher-efficacy therapies are often prescribed to patients with more active disease, which might make their results appear less favorable than they actually are
• Missing MRI data: Many patients did not have complete MRI information, though sensitivity analyses including MRI data showed similar results
• Side effects and safety: The study focused on effectiveness but did not compare side effects, risks, or safety profiles of the different treatments
• Newer treatments: Some newer MS therapies were not included because they weren't widely used during the study period (2006-2019)

The researchers noted that certain factors were challenging to balance completely between treatment groups, particularly disability levels for natalizumab patients and recent relapse activity for fingolimod patients. They statistically adjusted for these residual differences, but some uncertainty remains.

Actionable Advice for Patients

Based on these findings, patients with MS should consider the following when discussing treatment options with their neurologist:

1. Discuss treatment efficacy levels: Ask your doctor about the relative effectiveness of different therapy options, not just their side effect profiles
2. Consider your disease activity
3. Think long-term: Disability outcomes over years matter more than short-term relapse reduction alone
4. Review treatment response regularly
5. Balance benefits and risks: While efficacy is important, also consider safety monitoring requirements, administration method, and potential side effects
6. Participate in registries

Remember that treatment decisions should be personalized based on your specific disease characteristics, lifestyle, preferences, and risk tolerance. This study provides valuable evidence about comparative effectiveness, but individual responses to treatments can vary.

Source Information

Original Article Title: Effectiveness of multiple disease-modifying therapies in relapsing-remitting multiple sclerosis: causal inference to emulate a multiarm randomised trial

Authors: Ibrahima Diouf, Charles B Malpas, Sifat Sharmin, Izanne Roos, Dana Horakova, Eva Kubala Havrdova, Francesco Patti, Vahid Shaygannejad, Serkan Ozakbas, Sara Eichau, Marco Onofrj, Alessandra Lugaresi, Raed Alroughani, Alexandre Prat, Pierre Duquette, Murat Terzi, Cavit Boz, Francois Grand'Maison, Patrizia Sola, Diana Ferraro, Pierre Grammond, Bassem Yamout, Ayse Altintas, Oliver Gerlach, Jeannette Lechner-Scott, Roberto Bergamaschi, Rana Karabudak, Gerardo Iuliano, Christopher McGuigan, Elisabetta Cartechini, Stella Hughes, Maria Jose Sa, Claudio Solaro, Ludwig Kappos, Suzanne Hodgkinson, Mark Slee, Franco Granella, Koen de Gans, Pamela A McCombe, Radek Ampapa, Anneke van der Walt, Helmut Butzkueven, José Luis Sánchez-Menoyo, Steve Vucic, Guy Laureys, Youssef Sidhom, Riadh Gouider, Tamara Castillo-Trivino, Orla Gray, Eduardo Aguera-Morales, Abdullah Al-Asmi, Cameron Shaw, Talal M Al-Harbi, Tunde Csepany, Angel P Sempere, Irene Treviño Frenk, Elizabeth A Stuart, Tomas Kalincik

Publication: Journal of Neurology, Neurosurgery & Psychiatry, 2023;94:1004-1011

Note: This patient-friendly article is based on peer-reviewed research analyzing data from 23,236 patients across 35 countries followed for up to 5 years.