DOI: 10.25934/pr00010090
title: Monitoring white blood cells as an indicator to assess the risks of treatment failure in multiple sclerosis

description: Natalizumab is an antibody drug that targets a key molecule in white blood cells. The drug stops white blood cells from entering and crossing the inflamed blood vessels in the brain and the gut which may otherwise cause damage that results in Multiple Sclerosis (affecting 3 million people world wide, a million in the USA) and Crohn's Disease (affecting over 1 million people in the USA). This is highly effective in most people but the treatment is not infallible and some people will show disease breakthrough. Clinical attacks occur in about 20% of people, and about 40% of people exhibt new lesions that may cause an attack, within a year of treatment. A significant number of these people will develop anti-drug antibodies that can stop the drug working. Currently you have to wait at least 6 months and have disease breakthrough, which can cause disability, before you test for these anti-drug antibodies to check to see if they are persistent and at high levels. This signals the need to switch therapy to prevent further attacks. However as most people who fail treatment, already have persistent anti-drug antibodies within 3 months of recieving the drug, we believe it may be possible to detect this before disease and result and disability occurs.

When the drug works it traps white blood cells in the circulation and they increase in the blood. We have found that most people develop anti-drug antibodies within 4-8 weeks of treatment onset and we have found people who develop these antibodies and do not increase the level of white blood cells in the blood. We believe that a simple blood test to measure a subset of white blood cells will alert us to people who are at risk of treatment failure. Therefore we can start to monitor their anti-drug levels and disease more closely. This may allow us to change drug before disease shows itself and stop a few people from having a clinical attack and accumulating disability. We believe there will be a few individuals in the initial trials that we want to look at here, to see what happens to about 60 of 600 individuals who make anti-drug antibodies and compare these with the results to those found in treated and untreated individuals, without anti-drug antibodies, who were in the trial. We aim to monitor the individual responses as case studies to determine the percentage change in white blood cell numbers from baseline following treatment to determine if they increase, within 3 - 6 months, or do not increase so that we can set thresholds that predict the risk of treatment success/failure. We want to see if we can correlate lack of an increase in white blood cell numbers to the presence of anti-drug antibodies and to disease disease breakthrough. It is important to look at individual responses first, rather than looking at groups, as is typically done, because the latter approach tends to show no influence of anti-drug responses at a whole population level when they can be devastating for the individual.

Based on published literature, we know that monitoring white blood cell count can indicate success. We want to see if they can also be used as a early sign to spot people who will not get benefit for this very effective treatment, before they would fail treatment. This simple routine blood test could be introduced to help personalise effective treatment for people with multiple sclerosis.