Smouldering multiple sclerosis: an international consensus
Despite therapeutic suppression of relapses, people with MS often experience subtle deterioration, which extends beyond the definition of "progression independent of relapsing activity". Do you agree?
A few weeks ago, I did an MS-Selfie newsletter on MS treatment algorithms (‘Are MS treatment algorithms good or bad?’, 03 July 2024). I pointed out that the classifiers these algorithms use are flawed as they are not underpinned by biology and asked whether or not it was time for a change. The newsletter got a lot of feedback, and the discussion in the comments sections is worth reading.
We have started with the nomenclature and produced an International consensus paper. The paper is open-access so that you can download and read it. It includes several infographics that capture our intent. Please let me know if you understand the paper and have any questions.
The concepts underpinning this paper and our previous paper on smouldering MS (the real MS) are underpinned by one of my earliest and most popular MS-Selfie Newsletters (Getting Worse, 02-July-2021). So, to many of you, the concepts in this consensus paper should not be new.
The underlying message is that smouldering MS is the new bogeyman, and it needs all the attention it is being given. We need to measure it reliably and target it with new therapeutic strategies. I hope you agree.
It will be interesting to see if the broader MS community accept our terminology and recommendations. At least the Annals of Neurology editors and reviewers liked the paper; fingers crossed.
Paper 1 - International Consensus
Scalfari et al. Smouldering-Associated Worsening in Multiple Sclerosis: An International Consensus Statement on Definition, Biology, Clinical Implications, and Future Directions. Ann Neurol. 2024 Jul 25. doi: 10.1002/ana.27034.
Despite therapeutic suppression of relapses, multiple sclerosis (MS) patients often experience subtle deterioration, which extends beyond the definition of "progression independent of relapsing activity." We propose the concept of smouldering-associated-worsening (SAW), encompassing physical and cognitive symptoms, resulting from smouldering pathological processes, which remain unmet therapeutic targets. We provide a consensus-based framework of possible pathological substrates and manifestations of smouldering MS, and we discuss clinical, radiological, and serum/cerebrospinal fluid biomarkers for potentially monitoring SAW. Finally, we share considerations for optimizing disease surveillance and implications for clinical trials to promote the integration of smouldering MS into routine practice and future research efforts.
Paper 2 - Smouldering MS, the ‘Real MS’
Using a philosophical approach or deductive reasoning, we challenge the dominant clinico-radiological worldview that defines multiple sclerosis (MS) as a focal inflammatory disease of the central nervous system (CNS). We provide a range of evidence to argue that the 'real MS' is in fact driven primarily by a smouldering pathological disease process. In natural history studies and clinical trials, relapses and focal activity revealed by magnetic resonance imaging (MRI) in MS patients on placebo or on disease-modifying therapies (DMTs) were found to be poor predictors of long-term disease evolution and were dissociated from disability outcomes. In addition, the progressive accumulation of disability in MS can occur independently of relapse activity from early in the disease course. This scenario is underpinned by a more diffuse smouldering pathological process that may affect the entire CNS. Many putative pathological drivers of smouldering MS can be potentially modified by specific therapeutic strategies, an approach that may have major implications for the management of MS patients. We hypothesise that therapeutically targeting a state of 'no evident inflammatory disease activity' (NEIDA) cannot sufficiently prevent disability accumulation in MS, meaning that treatment should also focus on other brain and spinal cord pathological processes contributing to the slow loss of neurological function. This should also be complemented with a holistic approach to the management of other systemic disease processes that have been shown to worsen MS outcomes.
P.S. I have been away on holiday, hence the lack of activity. Hopefully, I will be back later this week with a Q&A session.
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Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or 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.
Great piece of work. 'Lotsa' questions.
1 'New' or 'enlarging T2 lesions' ought to be QUANTIFIED, no longer is it enough to say something has worsened or not, based on 'observations'. We need objectivity. Of course we do NOT use available technology to characterize VOLUME loss.
Most smoldering associated worsening is seemingly 'patient-driven' and therefore hugely subjective.
2 Why don't we simply accept the notion that the disease is relentlessly progressive, and whether it's defined under PIRA or SAW, or any other metric, the worsening is relentless over time and that DMTs have minimal or no role in the process ? This is probably true in about 70% of all MS patients, and whether it is reported or not by the patients themselves, one can look at the data and arrive at this conclusion. We honestly do not need more 'evidence' do we ? This could be true for MOST neurodegenerative disorders !!
3 Based on metrics such as reduced exercise endurance, exercise induced symptoms (aka Uhthoff's), worsening of fatigue, and generalized 'worsening', almost every single patient with multiple sclerosis can be considered to be worse from when they began the treatment. And if you consider Parkinson's or Alzheimer's I am sure the parallels are eerily similar.
4 We do not even test for cognitive function (no uniform, OP-based testing) in MS and certainly have zero consensus on the characterization of cortical lesions. Folks who have access to 7T magnets have reaped the benefit of such technology by producing gobs of publications with almost zero utility for most university-based clinics across the USA who do NOT have such fancy toys, let alone Europe. It is a mismatch at many different levels. It is like you have a GM cricket bat while mine is from some lumberyard, fashioned as one (cricketing analogy - you are from SA and I am from India, so we get this).
Jagannadha Avasarala
U of Kentucky Medical Center
Lexington, KY
I have secondary Progressive ms, I agree with the smouldering ms ,it’s quietly taking more of my functions away I haven’t had any relapses, but in the past 6 years, , I’ve lost the motor function in my left leg and foot, but haven’t been able to walk far in that time and now can’t walk at all, but thankfully so far my arms are still working , I love following your page as the neurologists I’ve seen, say there’s nothing to help me now