Biomarkers, cognition and PROMs in MS: Natalizumab compared to Rituximab

Project: Research


Multiple sclerosis (MS) is an inflammatory, degenerative disease of the central nervous system (CNS) which can present with a large variety of symptoms. The majority of patients with MS present with a single symptom, most commonly optic neuritis. Diagnosis is then confirmed by oligoclonal bands in cerebrospinal fluid combined with MRI-scanning. In 85 % of cases, the disease progresses in a relapsing-remitting fashion. Most of the drugs commonly used today are approved for treating relapsing-remitting MS.
During the last two decades, there has been great developments in the field of MS-treatment. In 2006 the Swedish Medical Products Agency approved Natalizumab for treatment of Multiple Sclerosis. It is a humanized monoclonal antibody against the adhesion molecule α4-integrin on the lymphocyte surface which binds to VLA-4 and osteopontin, thereby preventing lymphocytic access across the blood-brain-barrier. The drug is administered as an intravenous infusion every four weeks, and has shown great efficacy in studies as well as in clinical practice. However, an increase in progressive multifocal leukoencephalopathy, caused by the John Cunningham virus (JCV), were seen in natalizumab-treated patients.
Another major leap forward in MS-treatment is the use of Rituximab (RTX). Rituximab is an chimeric human/mouse anti-CD20 monoclonal antibody having been used in treatment of haematological malignancies for over 20 years. It leads to a depletion of CD20-positive B-cells through at least four different mechanisms of action – activation of a complement cascade causing the membrane attack complex (MAC) and thereby causing lysis, initiating interaction with natural killer cells causing cell-mediated cytotoxicity, allowing phagocytosis by macrophages and initiating a signalling pathway causing apoptosis. It is administered as an intravenous infusion every 6 – 12 months.
As a normal physiological process in ageing, the human central nervous system slowly degenerates. This can be measured in blood as well as in the cerebrospinal fluid. Patients with Multiple Sclerosis are known to have elevated levels of light weight neurofilaments in CSF, as well as in their blood. This is due to the nerve damage caused by inflammation in the CNS. It has been shown that Natalizumab effectively reduces the levels of NfL in CSF and in some cases even normalizing the levels of the biomarker. This has also been the case for RTX.
A known complication for patients with MS is what is called fatigue. Fatigue is poorly understood, and a common definition has yet to be reached, but symptoms include tiredness, lack of energy and general exhaustion. Theories of the cause include the general activation of the immune system as well as interruptions in nerve transmission because of the inflammatory nerve damage. There are well evaluated forms where patients grade their symptoms, thus giving a picture of the severity of their fatigue. However, to what extent this is preventable with newer therapies has not yet been investigated.
It seems that MS is not only a white brain matter disease. It has been shown that MS also causes cortical lesions. Through pathological examination as well as 7 tesla MRI-scans, it has been shown that the gray matter is under attack as well. In Sweden, 3 tesla and 1.5 tesla MRI-scans are used to monitor and evaluate the disease progression. Cortical lesions have been associated with cortical thinning and memory impairment.
These are generally considered highly effective treatments. However, head to head studies comparing the efficacy of the drugs in terms of NfL, 7T-MRI scans and fatigue has yet to be performed. The aim of this research is therefore to perform a head to head comparison between Natalizumab and Rituximab as a cross section study. Patients will be selected who has been under treatment with either NTZ or RTX for three consecutive years, are approximately the same age and are compatible regarding clinical activity and level of diability. Comparison of NfL in blood and CSF at diagnosis and at time of inclusion will be performed. To evaluate cortical lesions, 7T-tesla scans will be performed at Skånes Universitetssjukhus in Lund as a cross section. This will then be related to the level of fatigue the patients report.
Short titleNTZ versus RTX in MS
StatusNot started