Jordana Hughes1, Vilija Jokubaitis2,3, Alessandra Lugaresi4,5,6, Raymond Hupperts7, Guillermo Izquierdo8, Alexandre Prat9,10, Marc Girard9,10, Pierre Duquette9,10, Francois Grand'Maison11, Pierre Grammond12, Patrizia Sola13, Diana Ferraro13, Cristina Ramo-Tello14, Maria Trojano15, Mark Slee16, Vahid Shaygannejad17, Cavit Boz18, Jeanette Lechner-Scott19,20, Vincent Van Pesch21, Eugenio Pucci22, Claudio Solaro23, Freek Verheul24, Murat Terzi25, Franco Granella26, Daniele Spitaleri27, Raed Alroughani28, Jae-Kwan Jun1, Adam Fambiatos1, Anneke Van der Walt2,3, Helmut Butzkueven2,3,29, Tomas Kalincik1,3. 1. CORe, Department of Medicine, University of Melbourne, Parkville, Victoria, Australia. 2. Department of Medicine, University of Melbourne, Melbourne, Australia. 3. Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia. 4. Department of Neuroscience, Imaging and Clinical Sciences, University "G. d'Annunzio", Chieti, Italy. 5. Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy. 6. IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy. 7. Zuyderland Ziekenhuis, Sittard, the Netherlands. 8. Hospital Universitario Virgen Macarena, Sevilla, Spain. 9. Hopital Notre Dame, Montreal, Quebec, Canada. 10. CHUM and Universite de Montreal, Montreal, Quebec, Canada. 11. Neuro Rive-Sud, Greenfield Park, Quebec, Canada. 12. CISSS Chaudière-Appalache, Levis, Quebec, Canada. 13. Department of Neuroscience, Azienda Ospedaliera Universitaria, Modena, Italy. 14. Hospital Germans Trias i Pujol, Badalona, Spain. 15. Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, Italy. 16. Flinders University, Adelaide, Australia. 17. Isfahan University of Medical Sciences, Isfahan, Iran. 18. KTU Medical Faculty Farabi Hospital, Trabzon, Turkey. 19. School of Medicine and Public Health, University Newcastle, Newcastle, Australia. 20. Department of Neurology, John Hunter Hospital, Hunter New England Health, Newcastle, Australia. 21. Cliniques Universitaires Saint-Luc, Brussels, Belgium. 22. UOC Neurologia, Azienda Sanitaria Unica Regionale Marche-AV3, Macerata, Italy. 23. Ospedale P. A. Micone, Genova, Italy. 24. Groene Hart Ziekenhuis, Gouda, the Netherlands. 25. Medical Faculty, 19 Mayis University, Samsun, Turkey. 26. University of Parma, Parma, Italy. 27. Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati Avellino, Avellino, Italy. 28. Amiri Hospital, Kuwait City, Kuwait. 29. Department of Neurology, Box Hill Hospital, Monash University, Melbourne, Australia.
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 44 449 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.
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 44 449 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.
Authors: M Mateo Paz Soldán; Martina Novotna; Nuhad Abou Zeid; Nilufer Kale; Melih Tutuncu; Daniel J Crusan; Elizabeth J Atkinson; Aksel Siva; B Mark Keegan; Istvan Pirko; Sean J Pittock; Claudia F Lucchinetti; Brian G Weinshenker; Moses Rodriguez; Orhun H Kantarci Journal: Neurology Date: 2014-11-14 Impact factor: 9.910
Authors: G A SCHUMACHER; G BEEBE; R F KIBLER; L T KURLAND; J F KURTZKE; F MCDOWELL; B NAGLER; W A SIBLEY; W W TOURTELLOTTE; T L WILLMON Journal: Ann N Y Acad Sci Date: 1965-03-31 Impact factor: 5.691
Authors: Tomas Kalincik; Gary Cutter; Tim Spelman; Vilija Jokubaitis; Eva Havrdova; Dana Horakova; Maria Trojano; Guillermo Izquierdo; Marc Girard; Pierre Duquette; Alexandre Prat; Alessandra Lugaresi; Francois Grand'Maison; Pierre Grammond; Raymond Hupperts; Celia Oreja-Guevara; Cavit Boz; Eugenio Pucci; Roberto Bergamaschi; Jeannette Lechner-Scott; Raed Alroughani; Vincent Van Pesch; Gerardo Iuliano; Ricardo Fernandez-Bolaños; Cristina Ramo; Murat Terzi; Mark Slee; Daniele Spitaleri; Freek Verheul; Edgardo Cristiano; José Luis Sánchez-Menoyo; Marcela Fiol; Orla Gray; Jose Antonio Cabrera-Gomez; Michael Barnett; Helmut Butzkueven Journal: Brain Date: 2015-09-10 Impact factor: 13.501
Authors: H Butzkueven; J Chapman; E Cristiano; F Grand'Maison; M Hoffmann; G Izquierdo; D Jolley; L Kappos; T Leist; D Pöhlau; V Rivera; M Trojano; F Verheul; J P Malkowski Journal: Mult Scler Date: 2006-12 Impact factor: 6.312
Authors: Maria Trojano; Maria Liguori; Giovanni Bosco Zimatore; Roberto Bugarini; Carlo Avolio; Damiano Paolicelli; Fabrizio Giuliani; Francesca De Robertis; Maria Giovanna Marrosu; Paolo Livrea Journal: Ann Neurol Date: 2002-04 Impact factor: 10.422
Authors: Kathleen Hawker; Paul O'Connor; Mark S Freedman; Peter A Calabresi; Jack Antel; Jack Simon; Stephen Hauser; Emmanuelle Waubant; Timothy Vollmer; Hillel Panitch; Jiameng Zhang; Peter Chin; Craig H Smith Journal: Ann Neurol Date: 2009-10 Impact factor: 10.422
Authors: Tomas Kalincik; Ibrahima Diouf; Sifat Sharmin; Charles Malpas; Tim Spelman; Dana Horakova; Eva Kubala Havrdova; Maria Trojano; Guillermo Izquierdo; Alessandra Lugaresi; Alexandre Prat; Marc Girard; Pierre Duquette; Pierre Grammond; Vilija Jokubaitis; Anneke van der Walt; Francois Grand'Maison; Patrizia Sola; Diana Ferraro; Vahid Shaygannejad; Raed Alroughani; Raymond Hupperts; Murat Terzi; Cavit Boz; Jeannette Lechner-Scott; Eugenio Pucci; Vincent Van Pesch; Franco Granella; Roberto Bergamaschi; Daniele Spitaleri; Mark Slee; Steve Vucic; Radek Ampapa; Pamela McCombe; Cristina Ramo-Tello; Julie Prevost; Javier Olascoaga; Edgardo Cristiano; Michael Barnett; Maria Laura Saladino; Jose Luis Sanchez-Menoyo; Suzanne Hodgkinson; Csilla Rozsa; Stella Hughes; Fraser Moore; Cameron Shaw; Ernest Butler; Olga Skibina; Orla Gray; Allan Kermode; Tunde Csepany; Bhim Singhal; Neil Shuey; Imre Piroska; Bruce Taylor; Magdolna Simo; Carmen-Adella Sirbu; Attila Sas; Helmut Butzkueven Journal: Neurology Date: 2020-12-28 Impact factor: 9.910