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Results of the COMBAT-MS research

COMBAT-MS (an abbreviation for COMparison Between All immunoTherapies for Multiple Sclerosis, that is a comparison between all immunomodulatory treatments in MS) is an extensive research project aiming at investigating the efficacy, safety and patients satisfaction between the different pharmaceutical treatments for relapsing remitting multiple sclerosis (MS).

COMBAT-MS is divided into several different projects based on an ongoing (2017-2021) observational real-life study (a study where the choice of treatment is decided by the clinic) with participating centers from all university clinics in Sweden and linkage of registers in Sweden and in Pasadena, California, USA.

COMBAT-MS fulfills an important purpose since there are knowledge gaps today regarding efficacy, safety and patient satisfaction/quality of life and various MS treatments, especially over longer periods of time and in specific patient groups. This information is important when patients together with their neurologist are going to choose treatment. Compared with many other countries, Sweden has greater possibilities to carry out the studies needed to answer these questions, since we have a relatively equal healthcare systems across the country and several national healthcare records.

Although the deadline for the project is still a few years away, there are several issues that already can be answered. Below you find information about the results for completed and currently ongoing projects.

Around 3300 patients from the whole country is participating in the COMBAT-MS study. We are collecting more detailed information about the MS disease's severity and how patient perceive their health status (quality of life and satisfaction with their treatment). We will begin to be analyze these data in 2019.

Analysis of data from linkage of different registers, where all persons with MS who are on drug treatment in Sweden are included, has already started:

  • Mortality during treatment with the drug Mabthera (rituximab). From 2011 to 2018-02-28, two deaths have been recorded of a total of 3288 patient years (i.e. based on the number of individuals and their total treatment time). This is the same rate as the number of deaths in a control group from the general population, with the same age and gender distribution. The results were presented at the conference ECTRIMS in Berlin 2018 (Langer-Gould A and co-workers; ECTRIMS is a major European research network within MS).

Interpretation: When treating MS, Mabthera does not increase the risk of death. Follow-up during a longer period is needed to estimate the risk with longer treatment periods.

  • Cancer Risk during treatment with the drugs: Mabthera (rituximab), Tysabri (natalizumab) and Gilenya (fingolimod). All MS patients who started treatments during the years 2011-2016 were investigated and linked to cancer cases identified via the Swedish cancer register. The main outcome was all malignant cancer, but also specific cancers are investigated (including breast cancer). The results were presented at the conference ECTRIMS in Berlin 2018 by Alping P and co-workers and they could show that there was no significant increased risk for any of the drugs studied in terms of malignant cancer. The risk of breast cancer during treatment with Mabthera (rituximab) was comparable to the general population with only one case of 4050 patient years was identified. More detailed analysis of this cohort is in progress.

Interpretation: There is no signal that treatment with Mabthera, Tysabri or Gilenya in MS increases the risk of cancer. Follow-up for a longer period is needed to highlight the risk with longer treatment periods.

  • Risk of infection during treatment with Mabthera (rituximab), Tysabri (natalizumab) and Gilenya (fingolimod) compared to the older type of MS treatment with interferons. The study is based on data from the Swedish diagnostic register, where all diagnostic codes for all cases in specialized (i.e. no primary care) open or inpatient care are reported. The results were presented at the ECTRIMS conference in Berlin 2018 (Frisell T and co-workers) and show that the risk of infection of all types of infections is moderately elevated (approximately 50%) for persons treated with Mabthera (rituximab), Tysabri (natalizumab) and Gilenya (fingolimod) in comparison to those treated with interferons. The risk was somewhat, but not significantly elevated, with Mabthera compared to Tysabri and Gilenya. The risk of herpesvirus infection (e.g. shingles) was also increased risk, although the risk with Mabthera (rituximab) was slightly lower than that of Tysabri (natalizumab) and Gilenya (fingolimod). However, there was no significant difference in prescribing antibiotics for urinary and respiratory infections between the various drugs. Data will be analyzed more carefully to see if risk factors can be identified for increased risk of infection, such as degree of handicap or comorbidities.

Interpretation: High-efficacy MS treatments result in a moderate risk increase for infections compared to older MS treatments.

  • Pregnancy: There is currently insufficient information on the safety and risk on effects on fetal development for several of our newer MS treatments, which means that women with MS planning pregnancy can be faced with the choice of temporarily terminating their treatment with a risk of MS relapse or alternatively continue treatment despite the unclear risks on fetal development. In 2019 we will collect data on outcomes for all pregnancies where fertilization has taken place in close proximity to treatment termination or ongoing MS treatment, as well as risk of relapses during ongoing or recent pregnancy.

Results will be reported September 2019 at the conference ECTRIMS.

  • Dosing interval for Mabthera: Mabthera is currently one of the most common MS treatments in Sweden, but is only used to a limited extent for MS elsewhere in the world. When treated with Mabthera for rheumatoid arthritis, significantly higher doses are used than for MS. There are indications that the dose and dosage interval for Mabthera is important for the risk of infection. At the same time, it is of course very important to maintain a good treatment effect. A controlled study with a randomization between 6 and 12 months of treatment intervals after the first 2 years of treatment with Mabthera has recently been started, but it will take several years before the results of this study are available. In 2019, we will investigate whether there are any differences in relapse frequency between those treated with different doses and dosing intervals in the material available from the MS registry.

Results will be reported September 2019 at the conference ECTRIMS.

  • Anti-drug Antibodies: Pharmaceutical drugs consisting of proteins injected into the body (mainly interferons, Tysabri , Mabthera) pose a risk that the patients’ own immune system react against the drug and form anti-drug antibodies (ADA). These antibodies can reduce or completely block the desired treatment effect, so that the risk of relapses increases. For both interferons and Tysabri, there is currently an established routine for testing, analyzing and interpreting anti-drug antibodies, while the information on the extent to which Mabthera causes drug antibodies and how it affects the treatment effect is still limited. Within the framework of this study, we have set up a method for testing anti-drug antibodies against Mabthera and analyzing how they affect the treatment efficiency over a longer time.

Results: A first study about ADA against Mabthera has already been published, but to understand how ADA develop over a longer time and what it means for efficacy and safety of the treatment we will analyze the samples that are coming in during 2019. The results will be reported at ECTRIMS 2020.