Association of Inflammation and Disability Accrual in Patients with Progressive-Onset Multiple Sclerosis

Jordana Hughes, Vilija Jokubaitis, Alessandra Lugaresi, Raymond Hupperts, Guillermo Izquierdo, Alexandre Prat, Marc Girard, Pierre Duquette, Francois Grand'maison, Pierre Grammond, Patrizia Sola, DIana Ferraro, Cristina Ramo-Tello, Maria Trojano, Mark Slee, Vahid Shaygannejad, Cavit Boz, Jeanette Lechner-Scott, Vincent Van Pesch, Eugenio Pucci & 12 others Claudio Solaro, Freek Verheul, Murat Terzi, Franco Granella, Daniele Spitaleri, Raed Alroughani, Jae Kwan Jun, Adam Fambiatos, Anneke Van Der Walt, Helmut Butzkueven, Tomas Kalincik, for the MSBase Study Group

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Importance: The role of inflammatory disease activity as a determinant of disability in progressive-onset multiple sclerosis (MS) remains contested. Objective: To examine the association of superimposed relapses in progressive-onset MS on disease outcomes. Design, Setting, and Participants: Observational cohort study from MSBase, a prospectively collected, international database. Data were collected between January 1995 and February 2017. Analyses began in February 2017. From 44449 patients at time of extraction, 1419 eligible patients (31.9%) were identified for analysis. Inclusion criteria consisted of primary progressive MS (PPMS) or progressive-relapsing MS (PRMS), adult-onset disease, and minimum data set (including ≥3 visits with disability recorded, ≥3 months between second and last visit). Data were analyzed using multivariable regression models (Andersen-Gill) with mixed effects. Two sensitivity analyses to exclude both relapse-related disability progression and bout-onset progressive MS were performed. Exposures: Grouped according to presence or absence of relapse, defined as an acute episode of clinical worsening. Quantifiable disability change or correlation on imaging was not required to confirm relapse. Main Outcomes and Measures: Cumulative hazard of disability progression. Results: Patients with PRMS were younger than those with PPMS (mean [SD] age, 46 [15] vs 51 [10] years, Cohen d = 0.40) and demonstrated a mean lower Expanded Disability Status Scale score (mean [SD] score, 4.0 [3] vs 4.5 [2.5], Cohen d = 0.28) at inclusion. The ratio of men to women was similar in the PRMS and PPMS groups (252:301 vs 394:472). The overall mean (SD) age was 48 (11) years for men and 50 (10) years for women. Likelihood of confirmed disability progression was lower in patients with superimposed relapses (hazard ratio [HR], 0.83; 95% CI, 0.74-0.94; P =.003). Proportion of follow-up time spent on disease-modifying therapy significantly reduced the hazard of confirmed disability progression in the cohort with relapse (HR, 0.96; 95% CI, 0.94-0.99; P =.01) but not in those without relapse (HR, 1.02; 95% CI, 0.99-1.05; P =.26). When accounting for relapse-related progression, the association of disease-modifying therapy in the cohort with superimposed relapse was no longer observed (HR, 1.10; 95% CI, 0.96-1.24; P =.16). Conclusions and Relevance: In progressive-onset MS, superimposed relapses are associated with a lower risk of confirmed disability progression. This is most likely attributed to the association of disease-modifying therapy with the prevention of relapse-related disability accrual in patients with superimposed relapse. These findings suggest that inflammatory relapses are an important and modifiable determinant of disability accrual in progressive-onset disease.

Original languageEnglish
Pages (from-to)1407-1415
Number of pages9
JournalJAMA Neurology
Volume75
Issue number11
DOIs
Publication statusPublished - 1 Nov 2018

Cite this

Hughes, J., Jokubaitis, V., Lugaresi, A., Hupperts, R., Izquierdo, G., Prat, A., ... for the MSBase Study Group (2018). Association of Inflammation and Disability Accrual in Patients with Progressive-Onset Multiple Sclerosis. JAMA Neurology, 75(11), 1407-1415. https://doi.org/10.1001/jamaneurol.2018.2109
Hughes, Jordana ; Jokubaitis, Vilija ; Lugaresi, Alessandra ; Hupperts, Raymond ; Izquierdo, Guillermo ; Prat, Alexandre ; Girard, Marc ; Duquette, Pierre ; Grand'maison, Francois ; Grammond, Pierre ; Sola, Patrizia ; Ferraro, DIana ; Ramo-Tello, Cristina ; Trojano, Maria ; Slee, Mark ; Shaygannejad, Vahid ; Boz, Cavit ; Lechner-Scott, Jeanette ; Van Pesch, Vincent ; Pucci, Eugenio ; Solaro, Claudio ; Verheul, Freek ; Terzi, Murat ; Granella, Franco ; Spitaleri, Daniele ; Alroughani, Raed ; Jun, Jae Kwan ; Fambiatos, Adam ; Van Der Walt, Anneke ; Butzkueven, Helmut ; Kalincik, Tomas ; for the MSBase Study Group. / Association of Inflammation and Disability Accrual in Patients with Progressive-Onset Multiple Sclerosis. In: JAMA Neurology. 2018 ; Vol. 75, No. 11. pp. 1407-1415.
@article{fd03353d9b0c47449141ba6c923cf25a,
title = "Association of Inflammation and Disability Accrual in Patients with Progressive-Onset Multiple Sclerosis",
abstract = "Importance: The role of inflammatory disease activity as a determinant of disability in progressive-onset multiple sclerosis (MS) remains contested. Objective: To examine the association of superimposed relapses in progressive-onset MS on disease outcomes. Design, Setting, and Participants: Observational cohort study from MSBase, a prospectively collected, international database. Data were collected between January 1995 and February 2017. Analyses began in February 2017. From 44449 patients at time of extraction, 1419 eligible patients (31.9{\%}) were identified for analysis. Inclusion criteria consisted of primary progressive MS (PPMS) or progressive-relapsing MS (PRMS), adult-onset disease, and minimum data set (including ≥3 visits with disability recorded, ≥3 months between second and last visit). Data were analyzed using multivariable regression models (Andersen-Gill) with mixed effects. Two sensitivity analyses to exclude both relapse-related disability progression and bout-onset progressive MS were performed. Exposures: Grouped according to presence or absence of relapse, defined as an acute episode of clinical worsening. Quantifiable disability change or correlation on imaging was not required to confirm relapse. Main Outcomes and Measures: Cumulative hazard of disability progression. Results: Patients with PRMS were younger than those with PPMS (mean [SD] age, 46 [15] vs 51 [10] years, Cohen d = 0.40) and demonstrated a mean lower Expanded Disability Status Scale score (mean [SD] score, 4.0 [3] vs 4.5 [2.5], Cohen d = 0.28) at inclusion. The ratio of men to women was similar in the PRMS and PPMS groups (252:301 vs 394:472). The overall mean (SD) age was 48 (11) years for men and 50 (10) years for women. Likelihood of confirmed disability progression was lower in patients with superimposed relapses (hazard ratio [HR], 0.83; 95{\%} CI, 0.74-0.94; P =.003). Proportion of follow-up time spent on disease-modifying therapy significantly reduced the hazard of confirmed disability progression in the cohort with relapse (HR, 0.96; 95{\%} CI, 0.94-0.99; P =.01) but not in those without relapse (HR, 1.02; 95{\%} CI, 0.99-1.05; P =.26). When accounting for relapse-related progression, the association of disease-modifying therapy in the cohort with superimposed relapse was no longer observed (HR, 1.10; 95{\%} CI, 0.96-1.24; P =.16). Conclusions and Relevance: In progressive-onset MS, superimposed relapses are associated with a lower risk of confirmed disability progression. This is most likely attributed to the association of disease-modifying therapy with the prevention of relapse-related disability accrual in patients with superimposed relapse. These findings suggest that inflammatory relapses are an important and modifiable determinant of disability accrual in progressive-onset disease.",
author = "Jordana Hughes and Vilija Jokubaitis and Alessandra Lugaresi and Raymond Hupperts and Guillermo Izquierdo and Alexandre Prat and Marc Girard and Pierre Duquette and Francois Grand'maison and Pierre Grammond and Patrizia Sola and DIana Ferraro and Cristina Ramo-Tello and Maria Trojano and Mark Slee and Vahid Shaygannejad and Cavit Boz and Jeanette Lechner-Scott and {Van Pesch}, Vincent and Eugenio Pucci and Claudio Solaro and Freek Verheul and Murat Terzi and Franco Granella and Daniele Spitaleri and Raed Alroughani and Jun, {Jae Kwan} and Adam Fambiatos and {Van Der Walt}, Anneke and Helmut Butzkueven and Tomas Kalincik and {for the MSBase Study Group}",
year = "2018",
month = "11",
day = "1",
doi = "10.1001/jamaneurol.2018.2109",
language = "English",
volume = "75",
pages = "1407--1415",
journal = "JAMA Neurology",
issn = "2168-6149",
publisher = "American Medical Association (AMA)",
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}

Hughes, J, Jokubaitis, V, Lugaresi, A, Hupperts, R, Izquierdo, G, Prat, A, Girard, M, Duquette, P, Grand'maison, F, Grammond, P, Sola, P, Ferraro, DI, Ramo-Tello, C, Trojano, M, Slee, M, Shaygannejad, V, Boz, C, Lechner-Scott, J, Van Pesch, V, Pucci, E, Solaro, C, Verheul, F, Terzi, M, Granella, F, Spitaleri, D, Alroughani, R, Jun, JK, Fambiatos, A, Van Der Walt, A, Butzkueven, H, Kalincik, T & for the MSBase Study Group 2018, 'Association of Inflammation and Disability Accrual in Patients with Progressive-Onset Multiple Sclerosis' JAMA Neurology, vol. 75, no. 11, pp. 1407-1415. https://doi.org/10.1001/jamaneurol.2018.2109

Association of Inflammation and Disability Accrual in Patients with Progressive-Onset Multiple Sclerosis. / Hughes, Jordana; Jokubaitis, Vilija; Lugaresi, Alessandra; Hupperts, Raymond; Izquierdo, Guillermo; Prat, Alexandre; Girard, Marc; Duquette, Pierre; Grand'maison, Francois; Grammond, Pierre; Sola, Patrizia; Ferraro, DIana; Ramo-Tello, Cristina; Trojano, Maria; Slee, Mark; Shaygannejad, Vahid; Boz, Cavit; Lechner-Scott, Jeanette; Van Pesch, Vincent; Pucci, Eugenio; Solaro, Claudio; Verheul, Freek; Terzi, Murat; Granella, Franco; Spitaleri, Daniele; Alroughani, Raed; Jun, Jae Kwan; Fambiatos, Adam; Van Der Walt, Anneke; Butzkueven, Helmut; Kalincik, Tomas; for the MSBase Study Group.

In: JAMA Neurology, Vol. 75, No. 11, 01.11.2018, p. 1407-1415.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Association of Inflammation and Disability Accrual in Patients with Progressive-Onset Multiple Sclerosis

AU - Hughes, Jordana

AU - Jokubaitis, Vilija

AU - Lugaresi, Alessandra

AU - Hupperts, Raymond

AU - Izquierdo, Guillermo

AU - Prat, Alexandre

AU - Girard, Marc

AU - Duquette, Pierre

AU - Grand'maison, Francois

AU - Grammond, Pierre

AU - Sola, Patrizia

AU - Ferraro, DIana

AU - Ramo-Tello, Cristina

AU - Trojano, Maria

AU - Slee, Mark

AU - Shaygannejad, Vahid

AU - Boz, Cavit

AU - Lechner-Scott, Jeanette

AU - Van Pesch, Vincent

AU - Pucci, Eugenio

AU - Solaro, Claudio

AU - Verheul, Freek

AU - Terzi, Murat

AU - Granella, Franco

AU - Spitaleri, Daniele

AU - Alroughani, Raed

AU - Jun, Jae Kwan

AU - Fambiatos, Adam

AU - Van Der Walt, Anneke

AU - Butzkueven, Helmut

AU - Kalincik, Tomas

AU - for the MSBase Study Group

PY - 2018/11/1

Y1 - 2018/11/1

N2 - Importance: The role of inflammatory disease activity as a determinant of disability in progressive-onset multiple sclerosis (MS) remains contested. Objective: To examine the association of superimposed relapses in progressive-onset MS on disease outcomes. Design, Setting, and Participants: Observational cohort study from MSBase, a prospectively collected, international database. Data were collected between January 1995 and February 2017. Analyses began in February 2017. From 44449 patients at time of extraction, 1419 eligible patients (31.9%) were identified for analysis. Inclusion criteria consisted of primary progressive MS (PPMS) or progressive-relapsing MS (PRMS), adult-onset disease, and minimum data set (including ≥3 visits with disability recorded, ≥3 months between second and last visit). Data were analyzed using multivariable regression models (Andersen-Gill) with mixed effects. Two sensitivity analyses to exclude both relapse-related disability progression and bout-onset progressive MS were performed. Exposures: Grouped according to presence or absence of relapse, defined as an acute episode of clinical worsening. Quantifiable disability change or correlation on imaging was not required to confirm relapse. Main Outcomes and Measures: Cumulative hazard of disability progression. Results: Patients with PRMS were younger than those with PPMS (mean [SD] age, 46 [15] vs 51 [10] years, Cohen d = 0.40) and demonstrated a mean lower Expanded Disability Status Scale score (mean [SD] score, 4.0 [3] vs 4.5 [2.5], Cohen d = 0.28) at inclusion. The ratio of men to women was similar in the PRMS and PPMS groups (252:301 vs 394:472). The overall mean (SD) age was 48 (11) years for men and 50 (10) years for women. Likelihood of confirmed disability progression was lower in patients with superimposed relapses (hazard ratio [HR], 0.83; 95% CI, 0.74-0.94; P =.003). Proportion of follow-up time spent on disease-modifying therapy significantly reduced the hazard of confirmed disability progression in the cohort with relapse (HR, 0.96; 95% CI, 0.94-0.99; P =.01) but not in those without relapse (HR, 1.02; 95% CI, 0.99-1.05; P =.26). When accounting for relapse-related progression, the association of disease-modifying therapy in the cohort with superimposed relapse was no longer observed (HR, 1.10; 95% CI, 0.96-1.24; P =.16). Conclusions and Relevance: In progressive-onset MS, superimposed relapses are associated with a lower risk of confirmed disability progression. This is most likely attributed to the association of disease-modifying therapy with the prevention of relapse-related disability accrual in patients with superimposed relapse. These findings suggest that inflammatory relapses are an important and modifiable determinant of disability accrual in progressive-onset disease.

AB - Importance: The role of inflammatory disease activity as a determinant of disability in progressive-onset multiple sclerosis (MS) remains contested. Objective: To examine the association of superimposed relapses in progressive-onset MS on disease outcomes. Design, Setting, and Participants: Observational cohort study from MSBase, a prospectively collected, international database. Data were collected between January 1995 and February 2017. Analyses began in February 2017. From 44449 patients at time of extraction, 1419 eligible patients (31.9%) were identified for analysis. Inclusion criteria consisted of primary progressive MS (PPMS) or progressive-relapsing MS (PRMS), adult-onset disease, and minimum data set (including ≥3 visits with disability recorded, ≥3 months between second and last visit). Data were analyzed using multivariable regression models (Andersen-Gill) with mixed effects. Two sensitivity analyses to exclude both relapse-related disability progression and bout-onset progressive MS were performed. Exposures: Grouped according to presence or absence of relapse, defined as an acute episode of clinical worsening. Quantifiable disability change or correlation on imaging was not required to confirm relapse. Main Outcomes and Measures: Cumulative hazard of disability progression. Results: Patients with PRMS were younger than those with PPMS (mean [SD] age, 46 [15] vs 51 [10] years, Cohen d = 0.40) and demonstrated a mean lower Expanded Disability Status Scale score (mean [SD] score, 4.0 [3] vs 4.5 [2.5], Cohen d = 0.28) at inclusion. The ratio of men to women was similar in the PRMS and PPMS groups (252:301 vs 394:472). The overall mean (SD) age was 48 (11) years for men and 50 (10) years for women. Likelihood of confirmed disability progression was lower in patients with superimposed relapses (hazard ratio [HR], 0.83; 95% CI, 0.74-0.94; P =.003). Proportion of follow-up time spent on disease-modifying therapy significantly reduced the hazard of confirmed disability progression in the cohort with relapse (HR, 0.96; 95% CI, 0.94-0.99; P =.01) but not in those without relapse (HR, 1.02; 95% CI, 0.99-1.05; P =.26). When accounting for relapse-related progression, the association of disease-modifying therapy in the cohort with superimposed relapse was no longer observed (HR, 1.10; 95% CI, 0.96-1.24; P =.16). Conclusions and Relevance: In progressive-onset MS, superimposed relapses are associated with a lower risk of confirmed disability progression. This is most likely attributed to the association of disease-modifying therapy with the prevention of relapse-related disability accrual in patients with superimposed relapse. These findings suggest that inflammatory relapses are an important and modifiable determinant of disability accrual in progressive-onset disease.

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U2 - 10.1001/jamaneurol.2018.2109

DO - 10.1001/jamaneurol.2018.2109

M3 - Article

VL - 75

SP - 1407

EP - 1415

JO - JAMA Neurology

JF - JAMA Neurology

SN - 2168-6149

IS - 11

ER -