Results Summary

What was the research about?

Multiple sclerosis, or MS, is a health problem that affects the central nervous system. It causes problems with vision, balance, muscle control, and daily activities. Symptoms tend to last a short time at first but may become permanent.

Disease modifying therapies, or DMTs, help reduce MS disease activity. But DMTs vary in how effective and safe they are. People often switch DMTs until they find one that works. In other countries, doctors use a DMT called rituximab. In the United States, rituximab isn’t approved to treat MS.

In this study, the research team looked at the safety and effectiveness of rituximab compared with six other DMTs. The team looked separately at patients who started a DMT and patients who switched to a new DMT.

What were the results?

After three years, patients taking rituximab did about as well as those taking other DMTs. Overall, for patients taking these medicines, MS symptoms had less of an impact on well-being. The percentage of patients who had worsening disability from MS or whose MS affected their daily life was similar. But compared with other DMTs, more patients taking rituximab stayed on their medicine, and more had no MS symptoms. Also, compared with other DMTs, patients taking rituximab had:

  • Fewer MS relapses, or symptoms that returned after going away, except among patients starting natalizumab
  • Fewer MS relapses after childbirth

Patients who started rituximab were more satisfied with treatment than patients who started other DMTs, except natalizumab.

Patients taking rituximab and other DMTs didn’t differ in quality of life, cancer, heart problems, or problems during pregnancy.

Switching medicines. Patients who switched to rituximab had higher rates of a hospital stay for a serious infection than those who switched to other DMTs. Compared with switching to rituximab, patients who switched to:

  • Fingolimod had less fatigue
  • Natalizumab had faster cognitive processing

Satisfaction didn’t differ among patients who switched to rituximab or other DMTs, except dimethyl fumarate, which had lower satisfaction.

What did the research team do?

The research team enrolled 3,903 adults with MS. All received care at one of seven clinics in Sweden. Doctors prescribed a DMT to each patient. The team reviewed health records to see which DMTs patients took and to assess study outcomes. Among patients starting DMTs, the average age was 35, and 71 percent were women. Among patients switching DMTs, the average age was 40, and 72 percent were women.

To assess safety, the research team also looked at:

  • Registry data for 6,421 patients with MS in Sweden
  • Health records for 12,155 patients with MS in California

Patients with MS, caregivers, patient organizations, and doctors gave input during the study.

What were the limits of the study?

Fewer patients had worsening MS or safety outcomes than expected. As a result, it was hard to detect differences between DMTs.

Future research could compare DMTs for longer periods of time to better detect differences in outcomes.

How can people use the results?

Patients with MS and their doctors can use these results when considering DMTs to treat MS.

PCORI identified multiple sclerosis (MS) as an important research topic. People with MS, clinicians, and others wanted to learn how different treatment strategies, aimed at changing specific symptoms or the overall course of MS, affect patients’ symptoms and quality of life. To address this issue, PCORI launched an initiative in 2015 on Treatment of Multiple Sclerosis. The initiative funded this research project and others.

Final Research Report

This project's final research report is expected to be available by May 2024.

Journal Citations

Article Highlight: Through a research funding enhancement, which this study received in 2020 to quickly initiate new research related to COVID-19, the team comparing the safety and effectiveness of long-term medicines used to treat multiple sclerosis (MS) used its enhancement to see whether patients taking these drugs were more likely to be hospitalized or die from COVID-19 than the public. As reported in the Annals of Clinical and Translational Neurology, patients with MS treated with the drug rituximab were at increased risk of hospitalization but not ventilatory support or death from COVID‐19 compared to the general population.

Related Journal Citations

Peer-Review Summary

Peer review of PCORI-funded research helps make sure the report presents complete, balanced, and useful information about the research. It also assesses how the project addressed PCORI’s Methodology Standards. During peer review, experts read a draft report of the research and provide comments about the report. These experts may include a scientist focused on the research topic, a specialist in research methods, a patient or caregiver, and a healthcare professional. These reviewers cannot have conflicts of interest with the study.

The peer reviewers point out where the draft report may need revision. For example, they may suggest ways to improve descriptions of the conduct of the study or to clarify the connection between results and conclusions. Sometimes, awardees revise their draft reports twice or more to address all of the reviewers’ comments. 

Peer reviewers commented and the researchers made changes or provided responses. Those comments and responses included the following:

  • The reviewers stated that the report appeared to overstate the effectiveness of rituximab, which did not show substantial benefit on the primary outcomes. The reviewers advocated for the opening sections of the discussion and conclusion sections to summarize the study’s findings. The researchers implemented the suggested changes in the discussion, stating that off-label use of rituximab as a first- or second-line option did not result in reduced risk of disability progression and did not improve quality of life as compared with other disease modifying treatments (DMTs). The researchers also made changes in the conclusion, stating that three-year disability and patient-reported outcome measures displayed no or only small differences between DMTs.
  • The reviewers stated that describing this study as prospective is misleading, and that it is better described as a cohort study or as an observational study with a prospective follow-on cohort.  The researchers termed the study as an observational cohort.
  • The reviewers noted that the study reported unusually low relapse rates for rituximab and unexpectedly high rates for natalizumab, warranting a more thorough discussion of potential biases and limitations. The reviewers also identified unaddressed limitations and noted that statistical analysis was not adjusted for disease severity at baseline. The researchers replied that while natalizumab is known for low relapse rates, their data indicating higher rates were based on intention-to-treat analysis. They added a note in the limitations section of the report to emphasize the need for additional studies. They confirmed that they did adjust for baseline Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Impact Scale (MSIS-29) values, as well as the presence of relapses in the year before baseline. They agreed that there may still be residual confounding by disease severity even after this adjustment and have added a statement on this in the limitations section.
  • The reviewers identified several issues with the statistical analysis, particularly with the use of linear regression on summary data. They commented that the researchers needed to clarify the analytical approach. They further noted that the extent of missing data varied across treatment groups and could impact the study’s findings. The researchers explained that linear and log-linear models are commonly used in epidemiology for binary outcomes, noting that linear regression is preferred over logistic regression because it provides an intuitive measure of association: the difference in proportions. They acknowledged the problem of high missing data levels in their study but used multiple imputation methods to mitigate this issue. In their opinion, this method effectively handled missing data, especially when related to the DMT group, and was unbiased. They justified this approach by stating that the missing data were influenced by the treatment start year and previous pharmacovigilance projects at some clinics.
  • The reviewers requested clarification in the results section’s subsection on multiple sclerosis (MS) registry data enhancement. Specifically, they asked for the number of patients from the 3,012 in the validation study who were also in the COMBAT-MS study, and whether the reported methodologies, particularly chart comparison, were applied to COMBAT-MS data. The researchers stated that they re-designed the flow chart in the report to resolve the concerns raised. They clarified that chart review was performed on all participants fulfilling eligibility criteria based on data available in the MS registry as of January 2017 to align retrospective data across centers. 
  • The reviewers proposed the addition of a distinct section in the discussion, dedicated to summarizing the necessary caution in extrapolating the findings from the Swedish context to the United States. The researchers made changes and rephrased the paragraph to more clearly state that the external validity of results will be uncertain for other MS populations served by healthcare systems organized differently.

Conflict of Interest Disclosures

Project Information

Fredrik Piehl, MD, PhD
Karolinska Institute (Sweden)
$8,832,957
Rituximab in Multiple Sclerosis: A Comparative Study on Effectiveness, Safety, and Patient-Reported Outcomes

Key Dates

July 2016
September 2023
2016
2023

Study Registration Information

Note: This study had multiple sub-sites located within United States.

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Health Conditions Health Conditions These are the broad terms we use to categorize our funded research studies; specific diseases or conditions are included within the appropriate larger category. Note: not all of our funded projects focus on a single disease or condition; some touch on multiple diseases or conditions, research methods, or broader health system interventions. Such projects won’t be listed by a primary disease/condition and so won’t appear if you use this filter tool to find them. View Glossary
Populations Populations PCORI is interested in research that seeks to better understand how different clinical and health system options work for different people. These populations are frequently studied in our portfolio or identified as being of interest by our stakeholders. View Glossary
Intervention Strategy Intervention Strategies PCORI funds comparative clinical effectiveness research (CER) studies that compare two or more options or approaches to health care, or that compare different ways of delivering or receiving care. View Glossary
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Last updated: March 25, 2024