Comparing the Safety and Effectiveness of Different Medicines to Treat Multiple Sclerosis -- The COMBAT-MS Study

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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.

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

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.

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.

This COVID-19 study's final enhancement report is expected to be available by October 2023.