SAW - smoldering-MS-associated worsening
How can you tell me my MS is stable when I am getting worse on MRI? I have SAW. Do you agree?
Case study
How can you tell me my MS is stable when I am getting worse on MRI? Yes, I may not have had any recent relapses, and there are no new lesions on my MRI, but when I paid for “Enhanced MRI Analytics” to analyse my MRI scans from the last 5 years, the report came back showing worsening MS on several metrics. I have lost brain volume at a rate of 0.46% per year. The trajectories of my cortical grey volume, thalamic volume, corpus callosum cross-sectional area and upper spinal cord area are also outside what is expected for normal. More worrying is the data analysis showing I have numerous slowly expanding lesions. My MS is not stable; it is smoldering away. I must have smoldering-MS-associated worsening or SAW.
Prof G’s opinion
Please note the case study above is fictional. It represents what will happen in the near future as private MRI data analytical companies open for business. These companies will allow people with MS and other diseases to have their MRI scans analysed and provide metrics that are not available in routine clinical practice. As someone with MS, would you like more details on what is happening to your brain and spinal cord over and above the usual metrics of having Gd-enhancing or new T2 lesions reported?
The two studies below demonstrate the problem. The first study shows a worsening of MRI metrics in a cohort of patients with stable relapsing MS. I know some people call this silent progression. But how can this be a silent progression if it can be measured? This worsening does not fulfil the definition of PIRA (progression independent of relapse activity); PIRA implies physical worsening that can be measured with clinical outcome measures (EDSS, timed 25-foot walk or 9-hole peg test); these subjects were stable clinically.
At least reading the title, the second study suggests that ocrelizumab-treated patients with relapsing MS show brain volume loss rates similar to healthy ageing. The catch is in the term ‘similar’.
When you go into the paper and look at the small print, it is clear that the slope of the line of brain volume loss, or trajectory, in the study subjects on ocrelizumab, is faster than the age-matched healthy controls. Therefore, the brain volume loss trajectory in ocrelizumab-treated patients is not similar to healthy controls but occurs at an accelerated rate. It would be interesting to know if these study subjects had slowly expanding or paramagnetic rim lesions quantified. If yes, I suspect these were enlarging and not stable. I would also not be surprised if these subjects were put into a PET scanner that they would have ongoing microglial activation. Similarly, if their spinal fluid were analysed, they would still have local synthesis of oligoclonal IgG bands (OCBs). I am making the point that these patients have worsening MS as a group, which I would call SAW.
Although ocrelizumab is a very effective treatment that renders most patients NEIDA (no evident inflammatory disease activity), we need to go further. We cannot be complacent and must push for add-on trials and new therapies to tackle SAW. This is one of the next frontiers of MS research.
To avoid confusion around terminology, I would appreciate your opinion on using the acronym SAW (smoldering-MS associated worsening) to capture the phenomenon of worsening MS despite having no relapses or focal MRI activity. SAW includes PIRA (demonstrable physical worsening) and worsening captured by other metrics (e.g. MRI, retinal imaging, PET imaging, spinal fluid biomarkers, etc.). SAW can therefore be happening despite an individual being stable clinically, i.e. NEIDA, no RAW (relapse-associated worsening) and no PIRA (progression independent of relapse activity).
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Paper 1
Background: In relapsing-remitting multiple sclerosis (RRMS), cortical grey matter pathology relevantly contributes to long-term disability. Still, diffuse cortical inflammation cannot be detected with conventional MRI.
Objective: We aimed to assess microstructural damage of cortical grey matter over time and the relation to clinical disability as well as relapse activity in patients with RRMS using multiparametric quantitative (q)MRI techniques.
Methods: On 40 patients with RRMS and 33 age-matched and sex-matched healthy controls, quantitative T1, T2, T2* and proton density (PD) mapping was performed at baseline and follow-up after 2 years. Cortical qMRI parameter values were extracted with the FreeSurfer software using a surface-based approach. QMRI parameters, cortical thickness and white matter lesion (WML) load, as well as Expanded Disability Status Scale (EDSS) and relapse rate, were compared between time points.
Results: Over 2 years, significant increases of T1 (p≤0.001), PD (p≤0.001) and T2 (p=0.005) values were found in the patient, but not in the control group. At decreased relapse rate over time (p=0.001), cortical thickness, WML volume and EDSS remained unchanged.
Conclusion: Despite clinical stability, cortical T1, T2 and PD values increased over time, indicating progressive demyelination and increasing water content. These parameters represent promising surrogate parameters of diffuse cortical inflammation in RRMS.
Paper 2
Background: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system characterized by two major and interconnected hallmarks: inflammation and progressive neurodegeneration.
Objective: The aim of this work was to compare neurodegenerative processes, in the form of global and regional brain volume loss rates, in healthy controls (HCs) and in patients with relapsing MS (RMS) treated with ocrelizumab, which suppresses acute inflammation.
Methods: Whole brain, white matter, cortical gray matter, thalamic, and cerebellar volume loss rates were assessed in 44 HCs that were part of a substudy in the OPERA II randomized controlled trial (NCT01412333) and 59 patients with RMS enrolled in the same substudy as well as age- and sex-matched patients in OPERA I (NCT01247324) and II. Volume loss rates were computed using random coefficients models over a period of 2 years.
Results: Ocrelizumab-treated patients showed global and regional brain volume loss rates that were approaching that of HCs.
Conclusion: These findings are consistent with an important role of inflammation on overall tissue loss and the role of ocrelizumab in reducing this phenomenon.
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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have problems, please tell your healthcare professional, who will be able to help you.
Survey question: Could PIRA be expanded to include these biomarkers instead of just physical worsening?
MS researchers must all have the game Boggle - a word game in which players try to find as many words as they can from a grid of lettered dice. I’ve lost count of the various acronyms dreamed up by under worked MS researchers: RRMS, SPMS, PIRA, RAW, NEDA, PIRA, EDSS…… the list is endless. Surely the important point is that MS causes unrelenting brain tissue damage (sometimes slowly and sometimes quickly) and the mechanisms need to be understood and treated effectively. Do oncologists spend hours coming up with acronyms for the cancers they treat? (I suspect not). I want to see MS researchers with their white coats on identifying drugs to address the mechanisms and running trials, rather than moving tiles around on a Scrabble board. MS patients don’t give a shit about the latest acronym to describe the mechanisms damaging their brains, they’d rather hear “take these two / three treatments to stop any further damage and go enjoy your life”.