Smouldering-Associated Worsening in Multiple Sclerosis: An International Consensus Statement on Definition, Biology, Clinical Implications, and Future Directions

Antonio Scalfari¹, Anthony Traboulsee², Jiwon Oh³, Laura Airas⁴, Stefan Bittner⁵, Massimiliano Calabrese⁶, Jose Manuel Garcia Dominguez⁷, Cristina Granziera^{8

9}, Benjamin Greenberg¹⁰, Kerstin Hellwig¹¹, Zsolt Illes¹², Jan Lycke¹³, Veronica Popescu¹⁴, Francesca Bagnato^{15

16}, Gavin Giovannoni¹⁷

Affiliations

¹ Center of Neuroscience, Department of Medicine, Charing Cross Hospital, Imperial College, London, UK.
² University of British Columbia, Vancouver, Canada.
³ Division of Neurology, Department of Medicine, St Michael's Hospital, University of Toronto, Toronto, Canada.
⁴ University of Turku and Turku University Hospital, Turku, Finland.
⁵ Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network (Rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
⁶ University Hospital of Verona, Verona, Italy.
⁷ Hospital General Universitario Gregorio Marañón, Madrid, Spain.
⁸ Translational Imaging in Neurology (THiNK) Basel, Department of Biomedical Engineering, Faculty of Medicine, University of Basel, Basel, Switzerland.
⁹ Department of Neurology and MS Center, University Hospital Basel Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), Basel, Switzerland.
¹⁰ University of Texas Southwestern, Dallas, TX, USA.
¹¹ St. Josef Hospital, Ruhr University Bochum, Bochum, Germany.
¹² Department of Neurology, Odense University Hospital, University of Southern Denmark, Odense, Denmark.
¹³ Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
¹⁴ University MS Centre Pelt-Hasselt, Noorderhart Hospital, Belgium Hasselt University, Pelt, Belgium.
¹⁵ Neuroimaging Unit, Neuroimmunology Division, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁶ Department of Neurology, VA Hospital, TN Valley Healthcare System, Nashville, TN, USA.
¹⁷ Blizard Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK.

PMID: 39051525
DOI: 10.1002/ana.27034

Review

Smouldering-Associated Worsening in Multiple Sclerosis: An International Consensus Statement on Definition, Biology, Clinical Implications, and Future Directions

Antonio Scalfari et al. Ann Neurol. 2024 Nov.

. 2024 Nov;96(5):826-845.

doi: 10.1002/ana.27034. Epub 2024 Jul 25.

Authors

Affiliations

¹ Center of Neuroscience, Department of Medicine, Charing Cross Hospital, Imperial College, London, UK.
² University of British Columbia, Vancouver, Canada.
³ Division of Neurology, Department of Medicine, St Michael's Hospital, University of Toronto, Toronto, Canada.
⁴ University of Turku and Turku University Hospital, Turku, Finland.
⁵ Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network (Rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
⁶ University Hospital of Verona, Verona, Italy.
⁷ Hospital General Universitario Gregorio Marañón, Madrid, Spain.
⁸ Translational Imaging in Neurology (THiNK) Basel, Department of Biomedical Engineering, Faculty of Medicine, University of Basel, Basel, Switzerland.
⁹ Department of Neurology and MS Center, University Hospital Basel Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), Basel, Switzerland.
¹⁰ University of Texas Southwestern, Dallas, TX, USA.
¹¹ St. Josef Hospital, Ruhr University Bochum, Bochum, Germany.
¹² Department of Neurology, Odense University Hospital, University of Southern Denmark, Odense, Denmark.
¹³ Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
¹⁴ University MS Centre Pelt-Hasselt, Noorderhart Hospital, Belgium Hasselt University, Pelt, Belgium.
¹⁵ Neuroimaging Unit, Neuroimmunology Division, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁶ Department of Neurology, VA Hospital, TN Valley Healthcare System, Nashville, TN, USA.
¹⁷ Blizard Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK.

PMID: 39051525
DOI: 10.1002/ana.27034

Abstract

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. ANN NEUROL 2024;96:826-845.

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References

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Smouldering-Associated Worsening in Multiple Sclerosis: An International Consensus Statement on Definition, Biology, Clinical Implications, and Future Directions

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Smouldering-Associated Worsening in Multiple Sclerosis: An International Consensus Statement on Definition, Biology, Clinical Implications, and Future Directions

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References

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Grants and funding

LinkOut - more resources

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Medical