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. |
Professional Abstract
Objective
To compare the safety and effectiveness of rituximab versus other disease modifying therapies (DMTs) in reducing disease progression and disease-related impact on daily life in patients with relapsing-remitting multiple sclerosis (RRMS)
Study Design
Design Element | Description |
---|---|
Design | Observational: cohort study |
Population |
Prospective cohort for primary and secondary outcomes:
Additional retrospective data included to assess safety outcomes:
|
Interventions/ Comparators |
|
Outcomes |
Primary: disability progression; disease-related impact on daily life Secondary: relapse rate, proportion of patients remaining on DMT, proportion of patients with no evidence of disease activity, quality of life, fatigue, cognitive processing, treatment satisfaction Safety: hospitalization for infections, development of invasive cancer, major adverse cardiovascular events, adverse pregnancy or postpartum outcomes |
Timeframe | 3-year follow-up for primary outcomes |
This prospective observational study examined off-label use of rituximab versus other DMTs in patients with RRMS.
Researchers enrolled adults with RRMS who received care at one of seven clinics in Sweden. As part of routine care, clinicians prescribed a DMT to each patient. Patients were either taking a DMT for the first time or switching DMTs. To assess study outcomes, researchers reviewed health records from when patients started or switched DMTs and three years later. Researchers compared rituximab to other DMTs individually. They analyzed data separately for patients who started a DMT and patients who switched to a different DMT.
For the primary and secondary outcomes, the study included 3,903 adult patients with RRMS. Of patients starting a DMT, the average age was 35, and 71% were female. Of patients switching to a different DMT, the average age was 40, and 72% were female.
For analyses of safety outcomes, researchers included additional data from 6,421 adults with RRMS from the Swedish MS registry and 12,155 adults with RRMS from Kaiser Permanente Southern California.
Patients with RRMS, caregivers, patient organizations, and clinicians provided input throughout the study.
Results
At three years, the negative impact of MS on well-being lessened among patients overall. About 6% of patients had disability progression. The proportion of patients with disease-related impact on daily life or disability progression did not differ significantly between patients receiving rituximab and patients receiving other DMTs. However, the proportion of patients with no evidence of disease activity was higher for patients receiving rituximab compared with patients receiving other DMTs.
Also, compared with other DMTs, patients receiving rituximab had fewer relapses, except for patients starting natalizumab, and fewer postpartum relapses. Patients starting rituximab had higher treatment satisfaction than patients starting other DMTs, except those starting natalizumab.
Patients receiving rituximab and other DMTs did not differ significantly in other secondary and safety outcomes.
Switching Medications. Patients who switched to rituximab had higher rates of hospitalization for infection than patients who switched to other DMTs. Compared with patients who switched to rituximab, patients who switched to:
- Fingolimod had less fatigue
- Natalizumab had faster cognitive processing
Patients who switched to rituximab had higher treatment satisfaction than patients who switched to dimethyl fumarate; treatment satisfaction did not differ significantly among patients who switched to rituximab versus other DMTs.
Limitations
Researchers did not randomize participants to treatments; differences may be due to factors other than treatment. Also, disease progression and rare safety outcomes were less frequent than expected among patients in the study, which may have affected results.
Conclusions and Relevance
In this study, compared with other DMTs, rituximab was safe and effective for patients with RRMS.
Future Research Needs
Future research could compare rituximab versus other DMTs for longer periods of time to better detect differences in health and safety outcomes.
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. |
COVID-19-Related Study
Comparing the Safety of Medicines to Treat MS during the COVID-19 Pandemic
Results Summary
In response to the COVID-19 public health crisis in 2020, PCORI launched an initiative to enhance existing research projects so that they could offer findings related to COVID-19. The initiative funded this study and others.
What was this COVID-19 study about?
Multiple sclerosis, or MS, is a health problem that affects the brain and spinal cord. In MS, the immune system mistakenly attacks the coating around the nerves.
Disease modifying therapies, or DMTs, help to reduce the disease activity of MS. Examples include rituximab, fingolimod, and interferon. DMTs change how the body’s immune system works. But they may increase the risk for infection. During the COVID-19 pandemic, questions arose about whether taking DMTs could lead to worse health outcomes from COVID-19.
In this project, the research team used data from health records and registries for people with MS in California and Sweden. The team looked at COVID-19-related health outcomes and immune response.
What were the results?
Health outcomes. Overall, people with MS were not at higher risk for worse outcomes from COVID-19.
- Among young and middle-aged people with MS, the risk of death from any cause was similar before and during the pandemic.
- During the pandemic, people with and without MS had a similar risk for a hospital stay, a stay in an intensive care unit, and death from COVID-19.
- Among people with MS who took rituximab, people who had higher and more recent doses had a higher risk of having severe COVID-19. But their risk of a hospital stay didn’t differ compared with people with lower and less recent doses.
Immune response. Antibodies and T cells help the body fight infection. People with MS who took rituximab or fingolimod had lower antibody levels for COVID-19 than people who took interferon. But people who took some DMTs, like rituximab, had similar levels of T cells for COVID-19 as people who took other DMTs and people without MS.
What did the research team do?
The research team did three studies that looked at health outcomes among:
- 17,692 people with MS versus 86,176 people without MS in Sweden. This study used registry data.
- 1,895 people with MS who took rituximab in California; 54% were Hispanic. This study used health record data.
- 172 people with MS who took rituximab in Sweden. This study used registry data.
The research team did two studies looking at immune responses among:
- 2,480 people with MS who took different DMTs in Sweden. People had blood tests between July and October 2020.
- 632 people with MS treated at a Swedish clinic and 15 people without MS in Sweden. People completed surveys about COVID-19 symptoms. People also had blood tests when they filled out surveys and then again 4 and 12 weeks after getting a COVID-19 vaccine.
People with MS, family members, patient advocacy organizations, clinicians, and MS scientists provided input for this study.
What were the limits of the study?
Because COVID-19 is a new illness, the research team didn’t have the information they needed to determine how many people to include in each study. Studies may not have had enough people to find differences in some outcomes.
How can people use the results?
People with MS and their doctors can use these results when considering MS treatments during the pandemic.
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. |
Professional Abstract
In response to the COVID-19 public health crisis in 2020, PCORI launched an initiative to enhance existing research projects so that they could offer findings related to COVID-19. The initiative funded this study and others.
Background
Disease modifying therapies (DMTs) alter the immune response. Although DMTs reduce multiple sclerosis (MS) progression, they may increase the risk for infection. During the COVID-19 pandemic, questions arose about whether DMTs affect the COVID-19 immune response for people with MS.
Objective
(1) To determine COVID-19 clinical outcomes among people with MS and among those treated with DMTs; (2) To examine humoral and T-cell immunity development among people with MS treated with DMTs.
Study Design
Design Element | Description |
---|---|
Design |
5 observational and experimental cohort studies: Study 1: Retrospective observational cohort study Study 2: Retrospective observational cohort study Study 3: Experimental cohort study Study 4: Experimental cohort study Study 5: Registry linkage cohort study |
Population |
People with MS treated at Kaiser Permanente Southern California or living in Sweden Data from Kaiser Permanente Southern California, including electronic health records Data from people in Sweden, including electronic health records, study registries, and national health registries |
Outcomes |
Clinical outcomes: severity of COVID-19, hospitalization for COVID-19, all-cause mortality, admission to intensive care, death due to COVID-19 Immunologic outcomes: serological positivity to SARS-CoV-2 antigens and antibody levels, T-cell positivity to SARS-CoV-2 antigens |
Data Collection Timeframe |
Pre-pandemic observations included data from March 1, 2015, to January 31, 2020 Pandemic observations included data from January 1, 2020, to June 30, 2021 |
These studies explored clinical outcomes and immune response after COVID-19 infection and vaccination among people with MS. Researchers analyzed data from laboratory results, health records, and health registries.
To look at clinical outcomes following COVID-19 infection, researchers conducted three studies:
- Study 1 included health record data from Kaiser Permanente Southern California for 1,895 people with MS who took rituximab; 54% were Hispanic.
- Study 2 included data from the Swedish MS registry for 172 people with MS who took rituximab or other DMTs.
- Study 5 included Swedish nationwide registry data for 17,692 people with MS and 86,176 people without MS matched for age, sex, and region.
To look at immunologic outcomes for COVID-19 infection or vaccination, researchers conducted two studies:
- Study 3 included clinical data and blood samples collected between July and October 2020 from 2,480 people with MS who took different DMTs in Sweden.
- Study 4 included 632 people with MS treated at a large Swedish MS clinic and 15 people without MS. People completed questionnaires about COVID-19 symptoms. Researchers collected blood samples at baseline and 4 and 12 weeks after COVID-19 vaccination.
People with MS, family members, advocacy organizations, clinicians, and MS scientists provided input for the project.
Results
Clinical outcomes
- Study 1. Odds of developing severe COVID-19 increased for people with higher versus lower rituximab doses (odds ratio [OR]=6.28; 95% confidence interval [CI]: 1.38, 28.5) and shorter versus longer time since last infusion (OR=0.32; 95% CI: 0.15, 0.69).
- Study 2. The association between rituximab timing and dose with risk for hospitalization did not differ significantly between people who were and were not hospitalized.
- Study 5. The relative risk for mortality among people with MS did not differ significantly during versus before the pandemic. People with and without MS had a similar risk for hospitalization (0.6% versus 0.2%), intensive care unit admission (0.1% versus 0.02%), and death from COVID-19 (0.1% versus 0.04%).
Immunologic outcomes
- Study 3. COVID-19 antibody levels differed moderately across people with MS who took different DMTs. Antibody levels were lower among people who took rituximab or fingolimod versus interferon.
- Study 4. People with MS who took rituximab or other B-cell-depleting DMTs had an intact COVID-19 T-cell response but partially reduced antibody response, compared with people with MS who took other DMTs or people without MS.
Limitations
The studies may have been underpowered to detect differences in some outcomes.
Conclusions and Relevance
Relative risk of severe COVID-19 was similar among people with and without MS. Medications like rituximab were associated with a reduced antibody response but an intact T-cell response.
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. |
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:
- Reviewers pointed out the low rate of COVID-19 infection in this group of patients with multiple sclerosis (MS), noting that this would affect any study conclusions. They went on to state that the absence of a priori power calculations limited the conclusions that could be made. The researchers explained that this was a COVID-19-related enhancement of their main research project on MS and thus their ability to complete the study was significantly affected by the day-to-day changes in the pandemic, making power calculations untenable.
- The reviewers complained about the limited engagement of patients and other stakeholders in this study. The researchers acknowledged this but noted that they had substantial engagement of patients and other stakeholders in their main study of patients with MS and could not do the same separately for this enhancement project because of the short time window during the pandemic when this research had to be done. They did note that by the time the study started, there was anecdotal evidence that patients and clinicians were very interested in understanding how the COVID-19 virus could affect patients with MS.
- The reviewers criticized the analytic methods used in the study because the methods did not account for within-subject correlation on repeated-measures results or the binary nature of proportion measurement. The researchers disagreed with this assertion, noting that continuous-variable analytic techniques are relatively common for binary outcomes in current epidemiological research as a more intuitive comparison of two groups of patients.
Final Enhancement Report
This COVID-19 study's final enhancement report is expected to be available by October 2023.
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.
Results of This Project
Related Journal Citations
Peer-Review Summary
The Peer-Review Summary for this study will be posted here soon.
Conflict of Interest Disclosures
Project Information
Patient / Caregiver Partners
- Jacques Roussel, Jr, (LA, USA)
- Jacques Roussel Senior (LA, USA)
- Linda Roussel (LA, USA)
- Julie Stachowiak (Arizona, USA)
- Deanna Stoner, Rituxan for MS facebook page (online support group) (LA, USA)
- Eva Helmersson, Swedish patient (Stockholm, SW)
- Swedish Patient Advocacy Group (Sweden)
- Nicholas LaRocca PhD, National Multiple Sclerosis Society (New York City, NY USA)
Other Stakeholder Partners
- American Academy of Neurology representative - Gary Gronseth, MD (Minneapolis, Minnesota, USA)
- Saty Saty-Murti,MD FAAN, Health Policy Consultant, Neurologist (Santa Barbara California, USA)
- Nazia Rashid, PharmD, MS, Kaiser Permanente Drug Information Services
- Professor Gavin Giovannoni MBBCh, PhD, FCP (S.A., Neurol.), FRCP, FRCPath, Author of Barts MS Blog
- Jan Hillert, Swedish MS register (Sweden)
- Tomas Olsson, PI other IMSE studies (Sweden)
- Swedish MS Society (Sweden)