Results from the COMBAT-MS study

Many patients also are not eligible to join or decline participation in randomized trials. This makes it more difficult to extrapolate results to real world MS populations. A complementary way to study effect and safety of drugs is to do registry studies. Advantages with this type of studies are that they can be conducted over longer periods of time and include many more persons. However, there are also important drawbacks. Most important, it is more difficult to attribute effects (positive or negative) to the drug, since people who start different treatments might differ in aspects that impact treatment outcomes. Together, this means that the treating physicians do not have optimal evidence for recommending a certain type of treatment, especially when this also should include individual factors. Specifically looking at MS drugs, we primarily have information on to what degree they reduce the risk of relapses and the appearance of lesions – plaques - visible with magnetic resonance imaging. In contrast, information on how MS drugs affect the risk of developing neurological impairment or impact quality of life, especially over longer periods of time, is still scarce. This is problematic since these two aspects are the ones ranked highest by people with MS and their treating neurologists. Incomplete evidence likely is an important reason why drug preferences differ so much between different countries, regions and clinics. In fact, place of residence has greater influence on MS drug choice rather than what type of MS or individual characteristics you have. One aspect that makes MS clinics in Sweden and certain other locations, including Kaiser Permanente Southern California, different is that a relatively large proportion of MS patients initiate treatment with rituximab (Mabthera, Rixathon, Truxima). Rituximab is a drug approved for the treatment of rheumatoid arthritis, but with no formal approval for MS. The overall goal of the COMBAT-MS study has been to collect and analyze data relating to the benefit-risk balance with different drugs over a longer period of time. In particular, we wanted to see if there were advantages or risks with rituximab compared with regular MS-approved drugs.

How was the study conducted?

COMBAT-MS was an observational drug study conducted at all of Sweden's neurological university clinics. The study was funded by an American federal foundation (PCORI, Patient-Centered Outcomes Research Institute) whose overall purpose is to support high-quality scientific projects that improve treatment and care in various disease states. Therefore, COMBAT-MS has no commercial interests. One of the most important aspects of COMBAT-MS was that we chose very liberal criteria for participation, thereby aiming to include as many people with relapsing-remitting MS (RRMS) as possible. This also means that results are more likely to be of relevance for the heterogeneous real-world group of people with RRMS. Between 06/02/2017 and 06/30/2019, 3522 people consented to participate in COMBAT-MS, which is more than 80% of those who met criteria for participation. This number corresponds to approximately half of all MS patients in Sweden in this category, where the remaining half are followed at neurology clinics outside of university hospitals. The main objective of the study was to evaluate the outcome for those who started a first drug treatment (treatment naïve group) or who made a first drug switch (switch group), where some people could contribute information to both groups if they had switched treatment during the observation period. Overall, this meant that we had information of 2642 individuals in the treatment-naive group and 2531 in the switch group. Since results were compiled and compared at the group level and results are less reliable with small group sizes, we excluded treatment groups with less than 100 individuals. Therefore, not all drugs currently available were analyzed

Side effects and safety

The risk of side effects is an important factor to consider when selecting an MS drug. A unique aspect of the COMBAT-MS study was that we were able to include important safety outcomes by extracting data from high quality national health registries available in Sweden and KPSC. In this analysis we saw that highly effective MS drugs seemed to increase the risk of infections that require hospitalization in open or inpatient care. Compared to interferons, rituximab increased this risk by around 70%, while the risk increase for fingolimod and natalizumab was less pronounced. These two drugs, on the other hand, increased the risk of herpesvirus infections and shingles compared to interferons and rituximab. However, the overall absolute risk of infections was limited. For COMBAT-MS participants in the treatment-naive group, the risk of an infection requiring hospitalization was about 1 in 100 per year for those treated with rituximab, dimethyl fumarate, or natalizumab, and about half that with interferons or glatiramer acetate. In the switch group, the risk was twice as great with rituximab (2 in 100 per year), which was significantly higher than for the other treatments (dimethyl fumarate, natalizumab, fingolimod and teriflunomide). The risk of cancer or more serious cardiovascular disease did not appear to be affected by any MS drugs. Only 12 (treatment naïve) and 16 (switch group) were diagnosed with malignant cancer during the observation period. This low number means that it is difficult to compare across drugs. However, in a previous study where we analyzed all people with relapsing MS in Sweden, we could not find any significantly increased risk of cancer linked to the MS disease itself or the studied MS drugs (interferons, rituximab, fingolimod, natalizumab) compared with the general population. The number of serious cardiovascular disease events, such as stroke or myocardial infarction, in COMBAT-MS participants was even lower than the number of cancers, with no signal associated with any specific MS drug. Overall, these results suggest no or low risks of more serious treatment side effects, with the exception of an increased risk of hospital-treated infections with rituximab, and herpesvirus infections with fingolimod and natalizumab, compared to interferon treatment.

In these studies we could not find any evidence of increased risks for fetal malformations or other more serious effects on the child with exposure to MS drugs. However, the mothers’ risk of relapse after giving birth to their child was significantly lower among those who had been treated with rituximab before pregnancy, both compared to those who were treated with natalizumab before pregnancy and those who were untreated. These results indicate that treatment with rituximab may have advantages for women who are planning a pregnancy and want to minimize the risk of disease worsening after giving birth.

Conclusion

The COMBAT-MS study has shown that the risk of disease worsening with currently available treatments is less than we previously thought. These results are also better than contemporary data collected in other contexts and suggest that quality of healthcare impact long term MS outcomes. A positive result was also that there seems to be different ways to reach this goal, i.e., if allowing for drug switching no single treatment was better than others in avoiding increased neurological disability or experience reduced quality of life. At the same time, it is clear that a proportion of persons with MS needs new types of treatments that reduce risk of continuous disease deterioration and progressive MS. Intense research efforts are being made, but it is difficult to predict when such treatments may become available. There is also a great potential to further improve the benefit-risk balance with existing MS treatments. With better knowledge of who is at risk of having an insufficient effect or experiencing side effects with specific MS drugs, we can become better at selecting a suitable treatment from the start, i.e., to individualize the choice of treatment (also called precision medicine). Other important areas of improvement are understanding how lifestyle changes can improve the prognosis in MS. The data collected within COMBAT-MS will be an important tool for further studies to shed light on some of these aspects. All of this has been made possible thanks to the fantastic collaboration we have had with all COMBAT-MS participants from the north to the south in Sweden, especially with the challenges the COVID-19 pandemic brought, and all the extended participants in Sweden and at Kaiser Permanente Southern California in the US. A positive consequence was also that clinical follow-up routines in participating clinics have further improved thanks to the COMBAT-MS project. We look forward to continue collaborating with our patients in this important work!
 

• Executive Committee (EC): Project steering group
• Clinical Advisory Team (CAT)
• Scientific Advisory board and stakeholders