Midway evaluation - Hilde Marie Torgauten
Midway evaluation for the PhD degree at the University of Bergen for candidate Hilde Marie Torgauten
Hilde Marie Torgauten is affiliated with the Department of Clinical Medicine. Supervisors are Øivind Torkildsen and Kjell-Morten Myhr.
Aspects of disease modifying treatment with rituximab in multiple sclerosis
Background and purpose
Multiple sclerosis (MS) is a serious, autoimmune disease that affects the central nervous system (brain and spinal cord), debuting at the age of 20-40 and implying a lifelong risk of cumulative function loss for the patients. One of the most promising treatments is anti-B-cell antibodies such as rituximab, which is now the most widely used disease-modulating treatment in Norway in MS. Rituximab is off-label treatment and in several aspects there is a need for more knowledge about the treatment effect and adverse effects. The purpose of this project is to help shed light on areas where there is a lack of knowledge on clinically relevant aspects of this treatment strategy. In this project, we will investigate the effect and side effects of rituximab in a prospective cohort study, examine the vaccine response to corona vaccine in patients under rituximab treatment and compare the risk of rebound disease activity in patients in need of switching to rituximab from other highly effective treatment for MS.
In paper 1, a cohort of patients treated with rituximab against MS at Haukeland University Hospital (HUS) over a 4-year period was retreived from the Norwegian MS registry. Treatment effect was assessed with MRI and clinical activity, i.e. annual attack rate, and side effects were graded based on an international classification. In article 2, patients from Bergen and the surrounding area treated with rituximab against MS with HUS were identified in the MS registry and invited to provide a blood sample after vaccination against coronavirus (2 vaccine doses). The sample was analyzed with Enzyme-Linked Immunosorbent Assay (ELISA) for SARS-CoV-2 specific antibodies, and data from the MS registry and patient record for time since last treatment, lymphocyte count and b-cell count, and registered hospital admissions due to covid-19 -disease was obtained. In article 3, patients who participated in the national national Nevrovax project and who had previousely been shown to have a reduced humoral response after 2 doses of vaccine against covid-19, were offered a third vaccine dose at HUS or Oslo University Hospital (OUS). Humoral immune response was assessed after a 3rd dose with an in-house bead based flow cytometry method. In article 4, all patients at HUS and OUS who switched disease-modifying treatment from fingolimod to cladribine or rituximab through a periode of 2 years were identified through the Norwegian MS registry in a retrospective cohort study. Data from the registry on disease activity before and after changing treatment as well as possible predictors of disease activity (age, function, disease duration and previous treatment) were obtained.
The results in the first article indicate that the occurrence of disease activity during treatment with rituximab is low, that an increased risk of infections is the most common side effect and that the occurrence of serious side effects is rare.
The results in the second article are being finalized and so far show that the majority of patients under treatment with rituximab have a reduced humoral vaccine response. The number of patients admitted with severe covid disease in the cohort is low, which may indicate that the patients still have a protective effect from vaccination. In article three, the results show that the humoral vaccine response is still reduced after 3 doses of corona vaccine in patients with a reduced response after 2 doses, but that there was a moderate increase in antibody levels where 25% of the patients achieved detectable antibodies. The clinical relevance of such an increase must be assessed in further studies. Higher lymphocyte counts were associated with better antibody response in patients treated with rituximab. The third vaccine dose produced no serious side effects in this cohort. The results in article 4 show that the risk of rebound disease activity is higher when switching to cladribine than to rituximab from previously highly effective treatment with fingolimod (21% vs 0% rebound, p= 0.003). Risk of rebound was associated with younger age and higher disease activity measured by attack rate during previous treatment. The study indicates that if there is a need to change highly active MS treatment from fingolimod, rituximab may be a safer treatment choice than cladribine.