Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Feb 1;80(2):151-160.
doi: 10.1001/jamaneurol.2022.4655.

Association of Early Progression Independent of Relapse Activity With Long-term Disability After a First Demyelinating Event in Multiple Sclerosis

Carmen Tur  1 , Pere Carbonell-Mirabent  1 , Álvaro Cobo-Calvo  1 , Susana Otero-Romero  1 , Georgina Arrambide  1 , Luciana Midaglia  1 , Joaquín Castilló  1 , Ángela Vidal-Jordana  1 , Breogán Rodríguez-Acevedo  1 , Ana Zabalza  1 , Ingrid Galán  1 , Carlos Nos  1 , Annalaura Salerno  2 , Cristina Auger  2 , Deborah Pareto  2 , Manuel Comabella  1 , Jordi Río  1 , Jaume Sastre-Garriga  1 , Àlex Rovira  2 , Mar Tintoré  1 , Xavier Montalban  1
Affiliations

Association of Early Progression Independent of Relapse Activity With Long-term Disability After a First Demyelinating Event in Multiple Sclerosis

Carmen Tur et al. JAMA Neurol. .

Abstract

Importance: Progression independent of relapse activity (PIRA) is the main event responsible for irreversible disability accumulation in relapsing multiple sclerosis (MS).

Objective: To investigate clinical and neuroimaging predictors of PIRA at the time of the first demyelinating attack and factors associated with long-term clinical outcomes of people who present with PIRA.

Design, setting, and participants: This cohort study, conducted from January 1, 1994, to July 31, 2021, included patients with a first demyelinating attack from multiple sclerosis; patients were recruited from 1 study center in Spain. Patients were excluded if they refused to participate, had alternative diagnoses, did not meet protocol requirements, had inconsistent demographic information, or had less than 3 clinical assessments.

Exposures: Exposures included (1) clinical and neuroimaging features at the first demyelinating attack and (2) presenting PIRA, ie, confirmed disability accumulation (CDA) in a free-relapse period at any time after symptom onset, within (vs after) the first 5 years of the disease (ie, early/late PIRA), and in the presence (vs absence) of new T2 lesions in the previous 2 years (ie, active/nonactive PIRA).

Main outcomes and measures: Expanded Disability Status Scale (EDSS) yearly increase rates since the first attack and adjusted hazard ratios (HRs) for predictors of time to PIRA and time to EDSS 6.0.

Results: Of the 1128 patients (mean [SD] age, 32.1 [8.3] years; 781 female individuals [69.2%]) included in the study, 277 (25%) developed 1 or more PIRA events at a median (IQR) follow-up time of 7.2 (4.6-12.4) years (for first PIRA). Of all patients with PIRA, 86 of 277 (31%) developed early PIRA, and 73 of 144 (51%) developed active PIRA. Patients with PIRA were slightly older, had more brain lesions, and were more likely to have oligoclonal bands than those without PIRA. Older age at the first attack was the only predictor of PIRA (HR, 1.43; 95% CI, 1.23-1.65; P < .001 for each older decade). Patients with PIRA had steeper EDSS yearly increase rates (0.18; 95% CI, 0.16-0.20 vs 0.04; 95% CI, 0.02-0.05; P < .001) and an 8-fold greater risk of reaching EDSS 6.0 (HR, 7.93; 95% CI, 2.25-27.96; P = .001) than those without PIRA. Early PIRA had steeper EDSS yearly increase rates than late PIRA (0.31; 95% CI, 0.26-0.35 vs 0.13; 95% CI, 0.10-0.16; P < .001) and a 26-fold greater risk of reaching EDSS 6.0 from the first attack (HR, 26.21; 95% CI, 2.26-303.95; P = .009).

Conclusions and relevance: Results of this cohort study suggest that for patients with multiple sclerosis, presenting with PIRA after a first demyelinating event was not uncommon and suggests an unfavorable long-term prognosis, especially if it occurs early in the disease course.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Tur reported receiving grants from “La Caixa” Foundation Junior Leader incoming fellowship, Fundación Merck Salud (Spain) 2021 Merck’s Award for the Investigation in MS, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación de España Proyecto de Investigación, ECTRIMS 2015 ECTRIMS postdoctoral research fellowship, and the UK MS Society; speaker honoraria from Roche and Novartis; nonfinancial support from Biogen; being a steering committee member of the O’HAND trial and the Consensus Group on Follow-on DMTs; and being a member of the editorial board of Neurology. Dr Carbonell-Mirabent reported receiving grants from Biogen to Fundació Privada Cemcat for statistical analysis. Dr Cobo Calvo reported receiving grants from Instituto de Salud Carlos III, Spain; JR19/00007 during the conduct of the study. Dr Otero-Romero reported receiving a grant from Instituto de Salud Carlos III, Spain. Dr Arrambide reported receiving personal fees from Sanofi, Merck, and Horizon Therapeutics; nonfinancial support from Roche and Novartis; a research grant from Instituto de Salud Carlos III, Spain; travel support for scientific meetings from Novartis, Roche, and ECTRIMS; working as an editor for Europe of the Multiple Sclerosis Journal – Experimental, Translational and Clinical; working as a member of the International Women in Multiple Sclerosis Network executive committee; and working as a member of the European Biomarkers in MS Consortium steering committee. Dr Vidal-Jordana reported receiving grants from Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain; personal fees from Novartis, Roche, Merck, and Sanofi; and speaking honoraria and travel expenses from Novartis, Roche, Teva, Biogen, and Sanofi Genzyme. Dr Rodríguez-Acevedo reported receiving honoraria for consulting services from Wellspect. Dr Nos reported receiving steering committee fees from Hoffmann-La Roche; consulting fees from Sanofi; travel fees from Biogen Idec and F. Hoffmann-La Roche; speaker honoraria from Novartis; and funding from Novartis for registration for scientific meeting outside the submitted work. Dr Pareto reported receiving grants from Biogen Idec; speaking honoraria from Novartis and Sanofi Genzyme; and having a research contract with Biogen Idec. Dr Comabella reported receiving compensation for consulting services and speaking honoraria from Bayer Schering Pharma, Merck Serono, Biogen-Idec, Teva Pharmaceuticals, Sanofi-Aventis, and Novartis. Dr Río reported receiving speaking honoraria and personal compensation for participating on advisory boards from Biogen-Idec, Genzyme, Merck-Serono, Mylan, Novartis, Teva, Sanofi-Aventis, Roche, and Janssen. Dr Sastre-Garriga reported receiving personal fees for advisory board participation, speaking honoraria, and travel expenses from Novartis, Biogen, Sanofi, Celgene-BMS, Merck, Bial, Teva, Almirall, Genzyme, and Roche outside the submitted work. Dr Rovira reported receiving advisory board fees and/or speaker honoraria from Novartis, Synthetic MRI, Biogen, Bayer, Merck-Serono, Bristol Myers, OLEA Medical, Roche, TensorMedical, Sanofi Genzyme, and Teva Pharmaceuticals and being a shareholder in TensorMedical. Dr Tintoré reported receiving consulting and/or speaking honoraria from Almirall, Bayer, Schering Pharma, Biogen-Idec, Genzyme, Janssen, Merck-Serono, Novartis, Roche, Sanofi-Aventis, Viela Bio, and Teva Pharmaceuticals and being a co-editor of Multiple Sclerosis Journal – Experimental, Translational and Clinical. Dr Montalban reported received speaking honoraria, travel expenses for participation in scientific meetings, and/or being a steering committee member of or participated in advisory boards for Actelion, Alexion, Almirall, Bayer, Biogen, Bristol Myers Squibb, Celgene, EMD Serono, Genzyme, Hoffmann-La Roche, Immunic, Janssen, Medday, Merck, Mylan, Nervgen, Novartis, Oryzon Genomics, Sanofi-Genzyme, Sandoz, Teva Pharmaceuticals, TG Therapeutics, and NMSS outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Patient Flowchart and 6-Month Confirmed Disability Accumulation (CDA)
A, Patient flowchart from the whole deeply phenotyped cohort until the study cohort, with 1128 patients. B, Display of how the events of 6-month CDA were considered. The periods shaded in gray (6 months after the first attack and 3 months after any other event) represent the periods where any increase in Expanded Disability Status Scale (EDSS) score is considered to be associated with relapses. The time outside of these gray-shaded periods is referred to as periods free of relapses (PFRs). Any CDA within a PFR was considered a progression independent of relapse activity (PIRA) event, whereas any CDA outside a PFR was considered a relapse-associated worsening event. Patients with at least 1 CDA who had at least 1 PIRA event were considered patients with PIRA. Instead, patients with at least 1 CDA who never presented with a PIRA event were called patients with a relapse-associated worsening event. CDA was considered when a minimum EDSS increase was observed: 1.5, 1.0, or 0.5 points, with respect to a baseline/rebaseline EDSS score of 0, 1.0 to 5.0, or greater than 5.0, respectively.
Figure 2.
Figure 2.. Long-term Outcomes: Progression Independent of Relapse Activity (PIRA) vs No PIRA Comparison and Comparison Between PIRA Subgroups
A, Cumulative probability according to Kaplan-Meier estimations of experiencing the first PIRA event after the first demyelinating attack. Our estimations show that approximately 22 years after the first demyelinating event, 50% of all patients will have developed PIRA. B, Cumulative probabilities according to Kaplan-Meier estimations of reaching Expanded Disability Status Scale (EDSS) score of 6.0 in the PIRA and non-PIRA groups. C, Estimated EDSS trajectories over time for patients with and without PIRA. Both panels B and C show that patients with PIRA presented a much worse clinical evolution over time than those without PIRA. D, The main characteristics for the different PIRA subgroups. Early PIRA was associated with steeper EDSS trajectories over time and a higher risk of reaching EDSS 6.0 than late PIRA. Although patients with active PIRA and late PIRA (marginally) differed in terms of yearly EDSS increase rates, no significant differences were observed in survival models after adjusting for confounders. ARR indicates annualized relapse rate; HR, hazard ratio; SC, spinal cord. aP < .05. bP < .01.
Figure 3.
Figure 3.. Long-term Outcomes: Progression Independent of Relapse Activity (PIRA) vs Relapse-Associated Worsening (RAW) Comparison
A, Crude description of nonconfirmed Expanded Disability Status Scale (EDSS) score changes between baseline EDSS and last clinical visit, for patients with PIRA, RAW, and no confirmed disability accumulation (CDA). Patients with PIRA and RAW seem to be associated with a much heavier disability burden than patients without CDA, even in this unadjusted picture. When comparing PIRA and RAW, PIRA seems to be associated with greater increases in EDSS score than RAW. These findings were then confirmed through survival models of time to EDSS 6.0 (B). B, Kaplan-Meier curves of time to EDSS 6.0 from the first demyelinating attack, for patients with PIRA, RAW, and without CDA. All 3 survival curves were very different (log-rank test, χ22 = 44.11; P <.001). Patients with PIRA showed significantly faster rates of reaching EDSS 6.0 than patients with RAW (log-rank test, χ21 = 4.88; P <.03).
See this image and copyright information in PMC

Comment in

References

    1. Thompson AJ, Baranzini SE, Geurts J, Hemmer B, Ciccarelli O. Multiple sclerosis. Lancet. 2018;391(10130):1622-1636. https://linkinghub.elsevier.com/retrieve/pii/S0140673618304811. doi:10.1016/S0140-6736(18)30481-1 - DOI - PubMed
    1. Prosperini L, Ruggieri S, Haggiag S, Tortorella C, Pozzilli C, Gasperini C. Prognostic accuracy of NEDA-3 in long-term outcomes of multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2021;8(6):e1059. doi:10.1212/NXI.0000000000001059 - DOI - PMC - PubMed
    1. Cree BAC, Hollenbach JA, Bove R, et al. ; University of California, San Francisco MS-EPIC Team . Silent progression in disease activity-free relapsing multiple sclerosis. Ann Neurol. 2019;85(5):653-666. doi:10.1002/ana.25463 - DOI - PMC - PubMed
    1. 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):1132-1140. doi:10.1001/jamaneurol.2020.1568 - DOI - PMC - PubMed
    1. 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. doi:10.1177/2055217320966344 - DOI - PMC - PubMed

Publication types