Time to rethink worsening, formerly known as progressive, MS! #ResearchSpeak #MSBlog
One of the central hypotheses that underpins ‘progressive MS’ is that the oligoclonal bands in the cerebrospinal fluid (CSF) of pwMS is responsible for driving grey matter and spinal cord pathology. If we can’t clear the OCBs we will never prevent delayed onset of worsening, formerly known as progressive, MS. The problem with OCBs is that they are produced by long-lived plasma cells that are very difficult to eliminate. We know that none of the current high-efficacy treatments has an impact on OCBs; at least in the short term (< 10 years). This is why we are exploring different options to look for treatments that penetrate into the CNS that potentially target plasma cells.
The case study below from San Francisco supports other case reports and anecdotal data that high-efficacy therapies are not enough to prevent worsening, formerly known as progressive, MS. Steve Hauser treated a patient with active MS with Rituximab (anti-CD20) therapy and despite switching off new brain lesions this patient developed worsening disease. Although rituximab treatment reduced CSF levels of B cells there was evidence of ongoing CNS inflammation; OCBs were present in CSF even after nearly 7 years of anti-CD20 therapy and their were persistent T cells in the CSF. Clonally related B-cell populations were detected on both sides of the blood–brain barrier. Could these Rituximab-resistant B-cells have been plasma cells? Please remember, plasma cells don’t express CD20 on their surface. Surprisingly in this patient serial MRI examinations revealed a stable number of lesions in the brain (NEDA), but new spinal cord lesions. The latter is worrying as it may mean that simply doing annual brain MRI is insufficient to monitor the progression of MS. Unfortunately, there is no mention of CSF neurofilament levels in this patient. If I was a betting man, I would bet that the neurofilament levels would be raised. I suspect that CSF neurofilament levels will be good enough, if not better, than MRI as a marker of worsening MS.
The good news is that we have just been successful in getting a grant to test a new drug as an add-on treatment in MS to see if we can suppress plasma cell activity within the brain and spinal cord. It is clear that there is a massive unmet need for additional treatments in MS to target delayed worsening of the disease.
von Büdingen et al. Onset of secondary progressive MS after long-term rituximab therapy – a case report. Anals Clin Translational Neurology. First published: 20 December 2016 DOI: 10.1002/acn3.377
A patient with relapsing multiple sclerosis (RMS) was treated with a standard immunomodulatory therapy, but due to ongoing disease activity was switched to rituximab. Relapses ceased, but secondary progressive MS (SPMS) eventually appeared, associated with new focal spinal cord white matter lesions. Cerebrospinal fluid (CSF) showed persistent oligoclonal bands (OCB) and clonally related B cells in CSF and peripheral blood. The treatment escalation approach failed to prevent evolution to SPMS, raising the question of whether initiation of B-cell depleting therapy at the time of RMS diagnosis should be tested to more effectively address the immune pathology leading to SPMS.