Progression independent of relapse activity in adult patients with relapsing-remitting multiple sclerosis Review article
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Published:
Jun 30, 2024
Keywords:
multiple sclerosis, disability progression, disability accumulation, relapse-associated worsening, progression independent of relapse activity, progression independent of relapse and MRI activity
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Abstract
In clinical practice, multiple sclerosis is categorized based on clinical phenotypes for purposes such as the B.29 Therapeutic Drug Program, clinical trials, or drug registration. Concurrently, there is an increasing interest in perspectives that suggest the disease course of sclerosis multiplex should also, or perhaps primarily, be viewed as a continuum. This continuum comprises coexisting pathophysiological processes – pathological, remedial, or compensatory – that vary among individuals and evolve over time. Associated with these processes are fluctuations in disease activity or stabilization, as well as progression in terms of disease escalation and disability accumulation. Disability accumulation in patients with relapsing-remitting multiple sclerosis (RRMS) results from two concurrent factors: relapse-associated worsening and progression independent of relapse activity (PIRA). Studies, despite methodological differences, have demonstrated that progression can manifest early in the RRMS phase, with PIRA significantly contributing to long-term disability and serving as a negative predictor of disease trajectory. Some authors have identified PIRA as a distinct clinical phenotype, which should be diagnosed as early as feasible and considered when selecting or modifying Disease-Modifying Therapies. This article aims to clarify the terminology related to the progression of multiple sclerosis in relation to its established clinical phenotypes and to propose a unified definitions of PIRA and progression independent of relapse and MRI activity.
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References
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30. Kappos L, Butzkueven H, Wiendl H et al.; Tysabri® Observational Program (TOP) Investigators. Greater sensitivity to multiple sclerosis disability worsening and progression events using a roving versus a fixed reference value in a prospective cohort study. Mult Scler. 2018; 24(7): 963-73.
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2. Müller J, Cagol A, Lorscheider J et al. Harmonizing Definitions for Progression Independent of Relapse Activity in Multiple Sclerosis: A Systematic Review. JAMA Neurol. 2023; 80(11): 1232-45.
3. Leray E, Yaouanq J, Le Page E et al. Evidence for a two-stage disability progression in multiple sclerosis. Brain. 2010; 133(Pt 7): 1900-13.
4. Lassmann H, van Horssen J, Mahad D. Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Neurol. 2012; 8(11): 647-56.
5. Kuhlmann T , Mocciac M, Coetzee T et al. International Advisory Committee on Clinical Trials in Multiple Sclerosis. Multiple sclerosis progression: time for a new mechanism-driven framework. Lancet Neurol. 2023; 22(1): 78-88.
6. Vollmer TL, Nair KV, Williams IM et al. Multiple Sclerosis Phenotypes as a Continuum. The Role of Neurologic Reserve. Clin Pract. 2021; 11(4): 342-51.
7. Giovannoni G, Popescu V, Wuerfel J et al. Smouldering multiple sclerosis: the “real SM”. Ther Adv Neurol Disord. 2022; 15: 17562864211066752.
8. Kappos L, Wolinsky JS, Giovannoni G et al. Contribution of relapse-independent progression vs relapse-associated worsening to overall confirmed disability accumulation in typical relapsing multiple sclerosis in a pooled analysis of 2 randomized clinical trials. JAMA Neurol. 2020; 77 (9): 1132-40.
9. Lublin FD, Häring DA, Ganjgahi H et al. How patients with multiple sclerosis acquire disability. Brain. 2022; 145(9): 3147-61.
10. Portaccio E, Fonderico M, Aprea M et al. “Hidden” symptoms drive progression independent of relapse activity in relapsing-onset multiple sclerosis patients. Mult Scler. 2022; 28(3, suppl): 166.
11. Tur C, Carbonell-Mirabent P, Cobo-Calvo Á et al. Association of early progression independent of relapse activity with long-term disability after a first demyelinating event in multiple sclerosis. JAMA Neurol. 2023; 80(2): 151-60.
12. Cagol A, Schaedelin S, Barakovic M et al. Association of Brain Atrophy With Disease Progression Independent of Relapse Activity in Patients With Relapsing Multiple Sclerosis. JAMA Neurol. 2022; 79(7): 682-92.
13. Lublin FD, Reingold SC, Cohen JA et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014; 83(3): 278-86.
14. Cree BAC, Hollenbach JA, Bove R et al. Silent progression in disease activity-free relapsing multiple sclerosis. Ann Neurol. 2019; 85(5): 653-66.
15. Lublin FD, Coetzee T, Cohen JA et al. International Advisory Committee on Clinical Trials in MS. The 2013 clinical course descriptors for multiple sclerosis: a clarification. Neurology. 2020; 94(24): 1088-1092.
16. Prosperini L, Ruggieri S, Haggiag S et al. Prognostic accuracy of NEDA-3 in long-term outcomes of multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2021; 8(6): e1059.
17. Portaccio E, Bellinvia A, Fonderico M et al. Progression is independent of relapse activity in early multiple sclerosis: a real-life cohort study. Brain. 2022; 145(8): 2796-805.
18. Kapica-Topczewska K, Collin F, Tarasiuk J et al. Assessment of disability progression independent of relapse and brain MRI activity in patients with multiple sclerosis in Poland. J Clin Med. 2021;10(4): 868.
19. Massaneck L, Roifes L, Regner-Nelke L et al. Detecting ongoing disease activity in mildly affected multiple sclerosis patients under first-line therapies. Mult Scler Relat Disord. 2022; 63: 103927.
20. Ocampo-Pineda M, Barakovic M, Lu P et al. Patients with progression independent of relapse activity show increased degeneration of major white matter tracts. Mult Scler. 2022; 28(3 suppl): 1003-4.
21. Pisani A, Marastoni D, Mazziotti V et al. Focal cortical damage and intrathecal inflammation associate with disability progression independent of relapses in early multiple sclerosis: a preliminary study. Mult Scler. 2022; 28(3 suppl): 163.
22. Valsasina P, Rocca MA, Horsfield MA et al. Regional cervical cord atrophy and disability in multiple sclerosis: a voxel-based analysis. Radiology. 2013; 266(3): 853-61.
23. Lauerer M, McGinnis J, Bussas M et al. Prognostic value of spinal cord lesion measures in early relapsing-remitting multiple sclerosis. J Neurol Neurosurg Psychiatry. 2023; 95(1): 37-43.
24. Bischof A, Papinutto N, Keshavan A et al. Spinal Cord Atrophy Predicts Progressive Disease in Relapsing Multiple Sclerosis. Ann Neurol. 2022; 91(2): 268-81.
25. Lorscheider J, Buzzard K, Jokubaitis V et al. Defining secondary progressive multiple sclerosis. Brain. 2016; 139(Pt 9): 2395-405.
26. Bsteh G, Hegen H, Altmann P et al. Retinal layer thinning is reflecting disability progression independent of relapse activity in multiple sclerosis. Mult Scler J Exp Transl Clin. 2020; 6(4): 2055217320966344.
27. Abdelhak A, Benkert P, Schaedelin S et al. Neurofilament Light Chain Elevation and Disability Progression in Multiple Sclerosis. JAMA Neurol. 2023; 80(12): 1317-25.
28. Barro C, Healy B, Bose G et al. Prognostic value of neurofilament light and glial fibrillary acidic protein for disability worsening PIRA by age range in multiple sclerosis. Mult Scler. 2022; 28(3 suppl): 306.
29. Meier S, Willemse EAJ, Schaedelin S et al. Serum Glial Fibrillary Acidic Protein Compared With Neurofilament Light Chain as a Biomarker for Disease Progression in Multiple Sclerosis. JAMA Neurol. 2023; 80(3): 287-97.
30. Kappos L, Butzkueven H, Wiendl H et al.; Tysabri® Observational Program (TOP) Investigators. Greater sensitivity to multiple sclerosis disability worsening and progression events using a roving versus a fixed reference value in a prospective cohort study. Mult Scler. 2018; 24(7): 963-73.
31. Polman CH, Rudick RA. The multiple sclerosis functional composite: a clinically meaningful measure of disability. Neurology. 2010; 74(Suppl 3): S8-15.
32. Sharrad D, Chugh P, Slee M et al. Defining progression independent of relapse activity (PIRA) in adult patients with relapsing multiple sclerosis: A systematic review. Mult Scler Relat Disord. 2023; 78: 104899.