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1. Machine-learning-based prediction of disability progression in multiple sclerosis: An observational, international, multi-center study

Author

McGinnis, RS, De Brouwer, E, Becker, T, Werthen-Brabants, L, Dewulf, P, Iliadis, D, Dekeyser, C, Laureys, G, Van Wijmeersch, B, Popescu, V, Dhaene, T, Deschrijver, D, Waegeman, W, De Baets, B, Stock, M, Horakova, D, Patti, F, Izquierdo, G, Eichau, S, Girard, M, Prat, A, Lugaresi, A, Grammond, P, Kalincik, T, Alroughani, R, Grand'Maison, F, Skibina, O, Terzi, M, Lechner-Scott, J, Gerlach, O, Khoury, SJ, Cartechini, E, Van Pesch, V, Sà, MJ, Weinstock-Guttman, B, Blanco, Y, Ampapa, R, Spitaleri, D, Solaro, C, Maimone, D, Soysal, A, Iuliano, G, Gouider, R, Castillo-Triviño, T, Sánchez-Menoyo, JL, van der Walt, A, Oh, J, Aguera-Morales, E, Altintas, A, Al-Asmi, A, de Gans, K, Fragoso, Y, Csepany, T, Hodgkinson, S, Deri, N, Al-Harbi, T, Taylor, B, Gray, O, Lalive, P, Rozsa, C, McGuigan, C, Kermode, A, Sempere, AP, Mihaela, S, Simo, M, Hardy, T, Decoo, D, Hughes, S, Grigoriadis, N, Sas, A, Vella, N, Moreau, Y, Peeters, L, McGinnis, RS, De Brouwer, E, Becker, T, Werthen-Brabants, L, Dewulf, P, Iliadis, D, Dekeyser, C, Laureys, G, Van Wijmeersch, B, Popescu, V, Dhaene, T, Deschrijver, D, Waegeman, W, De Baets, B, Stock, M, Horakova, D, Patti, F, Izquierdo, G, Eichau, S, Girard, M, Prat, A, Lugaresi, A, Grammond, P, Kalincik, T, Alroughani, R, Grand'Maison, F, Skibina, O, Terzi, M, Lechner-Scott, J, Gerlach, O, Khoury, SJ, Cartechini, E, Van Pesch, V, Sà, MJ, Weinstock-Guttman, B, Blanco, Y, Ampapa, R, Spitaleri, D, Solaro, C, Maimone, D, Soysal, A, Iuliano, G, Gouider, R, Castillo-Triviño, T, Sánchez-Menoyo, JL, van der Walt, A, Oh, J, Aguera-Morales, E, Altintas, A, Al-Asmi, A, de Gans, K, Fragoso, Y, Csepany, T, Hodgkinson, S, Deri, N, Al-Harbi, T, Taylor, B, Gray, O, Lalive, P, Rozsa, C, McGuigan, C, Kermode, A, Sempere, AP, Mihaela, S, Simo, M, Hardy, T, Decoo, D, Hughes, S, Grigoriadis, N, Sas, A, Vella, N, Moreau, Y, and Peeters, L

Abstract

BACKGROUND: Disability progression is a key milestone in the disease evolution of people with multiple sclerosis (PwMS). Prediction models of the probability of disability progression have not yet reached the level of trust needed to be adopted in the clinic. A common benchmark to assess model development in multiple sclerosis is also currently lacking. METHODS: Data of adult PwMS with a follow-up of at least three years from 146 MS centers, spread over 40 countries and collected by the MSBase consortium was used. With basic inclusion criteria for quality requirements, it represents a total of 15, 240 PwMS. External validation was performed and repeated five times to assess the significance of the results. Transparent Reporting for Individual Prognosis Or Diagnosis (TRIPOD) guidelines were followed. Confirmed disability progression after two years was predicted, with a confirmation window of six months. Only routinely collected variables were used such as the expanded disability status scale, treatment, relapse information, and MS course. To learn the probability of disability progression, state-of-the-art machine learning models were investigated. The discrimination performance of the models is evaluated with the area under the receiver operator curve (ROC-AUC) and under the precision recall curve (AUC-PR), and their calibration via the Brier score and the expected calibration error. All our preprocessing and model code are available at https://gitlab.com/edebrouwer/ms_benchmark, making this task an ideal benchmark for predicting disability progression in MS. FINDINGS: Machine learning models achieved a ROC-AUC of 0⋅71 ± 0⋅01, an AUC-PR of 0⋅26 ± 0⋅02, a Brier score of 0⋅1 ± 0⋅01 and an expected calibration error of 0⋅07 ± 0⋅04. The history of disability progression was identified as being more predictive for future disability progression than the treatment or relapses history. CONCLUSIONS: Good discrimination and calibration performance on an external validation s

Published
2024

2. The risk of secondary progressive multiple sclerosis is geographically determined but modifiable

Author

Sharmin, S, Roos, I, Simpson-Yap, S, Malpes, C, Sanchez, MM, Ozakbas, S, Horakova, D, Havrdova, EK, Patti, F, Alroughani, R, Izquierdo, G, Eichau, S, Boz, C, Zakaria, M, Onofrj, M, Lugaresi, A, Weinstock-Guttman, B, Prat, A, Girard, M, Duquette, P, Terzi, M, Amato, MP, Karabudak, R, Grand'Maison, F, Khoury, SJ, Grammond, P, Lechner-Scott, J, Buzzard, K, Skibina, O, van der Walt, A, Butzkueven, H, Turkoglu, R, Altintas, A, Maimone, D, Kermode, A, Shalaby, N, Pesch, VV, Butler, E, Sidhom, Y, Gouider, R, Mrabet, S, Gerlach, O, Soysal, A, Barnett, M, Kuhle, J, Hughes, S, Sa, MJ, Hodgkinson, S, Oreja-Guevara, C, Ampapa, R, Petersen, T, Ramo-Tello, C, Spitaleri, D, McCombe, P, Taylor, B, Prevost, J, Foschi, M, Slee, M, McGuigan, C, Laureys, G, Hijfte, LV, de Gans, K, Solaro, C, Oh, J, Macdonell, R, Aguera-Morales, E, Singhal, B, Gray, O, Garber, J, Wijmeersch, BV, Simu, M, Castillo-Trivino, T, Sanchez-Menoyo, JL, Khurana, D, Al-Asmi, A, Al-Harbi, T, Deri, N, Fragoso, Y, Lalive, PH, Sinnige, LGF, Shaw, C, Shuey, N, Csepany, T, Sempere, AP, Moore, F, Decoo, D, Willekens, B, Gobbi, C, Massey, J, Hardy, T, Parratt, J, Kalincik, T, Sharmin, S, Roos, I, Simpson-Yap, S, Malpes, C, Sanchez, MM, Ozakbas, S, Horakova, D, Havrdova, EK, Patti, F, Alroughani, R, Izquierdo, G, Eichau, S, Boz, C, Zakaria, M, Onofrj, M, Lugaresi, A, Weinstock-Guttman, B, Prat, A, Girard, M, Duquette, P, Terzi, M, Amato, MP, Karabudak, R, Grand'Maison, F, Khoury, SJ, Grammond, P, Lechner-Scott, J, Buzzard, K, Skibina, O, van der Walt, A, Butzkueven, H, Turkoglu, R, Altintas, A, Maimone, D, Kermode, A, Shalaby, N, Pesch, VV, Butler, E, Sidhom, Y, Gouider, R, Mrabet, S, Gerlach, O, Soysal, A, Barnett, M, Kuhle, J, Hughes, S, Sa, MJ, Hodgkinson, S, Oreja-Guevara, C, Ampapa, R, Petersen, T, Ramo-Tello, C, Spitaleri, D, McCombe, P, Taylor, B, Prevost, J, Foschi, M, Slee, M, McGuigan, C, Laureys, G, Hijfte, LV, de Gans, K, Solaro, C, Oh, J, Macdonell, R, Aguera-Morales, E, Singhal, B, Gray, O, Garber, J, Wijmeersch, BV, Simu, M, Castillo-Trivino, T, Sanchez-Menoyo, JL, Khurana, D, Al-Asmi, A, Al-Harbi, T, Deri, N, Fragoso, Y, Lalive, PH, Sinnige, LGF, Shaw, C, Shuey, N, Csepany, T, Sempere, AP, Moore, F, Decoo, D, Willekens, B, Gobbi, C, Massey, J, Hardy, T, Parratt, J, and Kalincik, T

Abstract

Geographical variations in the incidence and prevalence of multiple sclerosis have been reported globally. Latitude as a surrogate for exposure to ultraviolet radiation but also other lifestyle and environmental factors are regarded as drivers of this variation. No previous studies evaluated geographical variation in the risk of secondary progressive multiple sclerosis, an advanced form of multiple sclerosis that is characterized by steady accrual of irreversible disability. We evaluated differences in the risk of secondary progressive multiple sclerosis in relation to latitude and country of residence, modified by high-to-moderate efficacy immunotherapy in a geographically diverse cohort of patients with relapsing-remitting multiple sclerosis. The study included relapsing-remitting multiple sclerosis patients from the global MSBase registry with at least one recorded assessment of disability. Secondary progressive multiple sclerosis was identified as per clinician diagnosis. Sensitivity analyses used the operationalized definition of secondary progressive multiple sclerosis and the Swedish decision tree algorithm. A proportional hazards model was used to estimate the cumulative risk of secondary progressive multiple sclerosis by country of residence (latitude), adjusted for sex, age at disease onset, time from onset to relapsing-remitting phase, disability (Multiple Sclerosis Severity Score) and relapse activity at study inclusion, national multiple sclerosis prevalence, government health expenditure, and proportion of time treated with high-to-moderate efficacy disease-modifying therapy. Geographical variation in time from relapsing-remitting phase to secondary progressive phase of multiple sclerosis was modelled through a proportional hazards model with spatially correlated frailties. We included 51 126 patients (72% female) from 27 countries. The median survival time from relapsing-remitting phase to secondary progressive multiple sclerosis among all patients wa

Published
2023

3. Variability of the response to immunotherapy among subgroups of patients with multiple sclerosis

Author

Diouf, I, Malpas, CB, Sharmin, S, Roos, I, Horakova, D, Havrdova, EK, Patti, F, Shaygannejad, V, Ozakbas, S, Izquierdo, G, Eichau, S, Onofrj, M, Lugaresi, A, Alroughani, R, Prat, A, Girard, M, Duquette, P, Terzi, M, Boz, C, Grand'Maison, F, Hamdy, S, Sola, P, Ferraro, D, Grammond, P, Turkoglu, R, Buzzard, K, Skibina, O, Yamout, B, Altintas, A, Gerlach, O, van Pesch, V, Blanco, Y, Maimone, D, Lechner-Scott, J, Bergamaschi, R, Karabudak, R, Iuliano, G, McGuigan, C, Cartechini, E, Barnett, M, Hughes, S, Sa, MJ, Solaro, C, Kappos, L, Ramo-Tello, C, Cristiano, E, Hodgkinson, S, Spitaleri, D, Soysal, A, Petersen, T, Slee, M, Butler, E, Granella, F, de Gans, K, McCombe, P, Ampapa, R, Van Wijmeersch, B, van der Walt, A, Butzkueven, H, Prevost, J, Sinnige, LGF, Sanchez-Menoyo, JL, Vucic, S, Laureys, G, Van Hijfte, L, Khurana, D, Macdonell, R, Gouider, R, Castillo-Trivino, T, Gray, O, Aguera-Morales, E, Al-Asmi, A, Shaw, C, Deri, N, Al-Harbi, T, Fragoso, Y, Csepany, T, Sempere, AP, Trevino-Frenk, I, Schepel, J, Moore, F, Kalincik, T, Diouf, I, Malpas, CB, Sharmin, S, Roos, I, Horakova, D, Havrdova, EK, Patti, F, Shaygannejad, V, Ozakbas, S, Izquierdo, G, Eichau, S, Onofrj, M, Lugaresi, A, Alroughani, R, Prat, A, Girard, M, Duquette, P, Terzi, M, Boz, C, Grand'Maison, F, Hamdy, S, Sola, P, Ferraro, D, Grammond, P, Turkoglu, R, Buzzard, K, Skibina, O, Yamout, B, Altintas, A, Gerlach, O, van Pesch, V, Blanco, Y, Maimone, D, Lechner-Scott, J, Bergamaschi, R, Karabudak, R, Iuliano, G, McGuigan, C, Cartechini, E, Barnett, M, Hughes, S, Sa, MJ, Solaro, C, Kappos, L, Ramo-Tello, C, Cristiano, E, Hodgkinson, S, Spitaleri, D, Soysal, A, Petersen, T, Slee, M, Butler, E, Granella, F, de Gans, K, McCombe, P, Ampapa, R, Van Wijmeersch, B, van der Walt, A, Butzkueven, H, Prevost, J, Sinnige, LGF, Sanchez-Menoyo, JL, Vucic, S, Laureys, G, Van Hijfte, L, Khurana, D, Macdonell, R, Gouider, R, Castillo-Trivino, T, Gray, O, Aguera-Morales, E, Al-Asmi, A, Shaw, C, Deri, N, Al-Harbi, T, Fragoso, Y, Csepany, T, Sempere, AP, Trevino-Frenk, I, Schepel, J, Moore, F, and Kalincik, T

Abstract

BACKGROUND AND PURPOSE: This study assessed the effect of patient characteristics on the response to disease-modifying therapy (DMT) in multiple sclerosis (MS). METHODS: We extracted data from 61,810 patients from 135 centers across 35 countries from the MSBase registry. The selection criteria were: clinically isolated syndrome or definite MS, follow-up ≥ 1 year, and Expanded Disability Status Scale (EDSS) score ≥ 3, with ≥1 score recorded per year. Marginal structural models with interaction terms were used to compare the hazards of 12-month confirmed worsening and improvement of disability, and the incidence of relapses between treated and untreated patients stratified by their characteristics. RESULTS: Among 24,344 patients with relapsing MS, those on DMTs experienced 48% reduction in relapse incidence (hazard ratio [HR] = 0.52, 95% confidence interval [CI] = 0.45-0.60), 46% lower risk of disability worsening (HR = 0.54, 95% CI = 0.41-0.71), and 32% greater chance of disability improvement (HR = 1.32, 95% CI = 1.09-1.59). The effect of DMTs on EDSS worsening and improvement and the risk of relapses was attenuated with more severe disability. The magnitude of the effect of DMT on suppressing relapses declined with higher prior relapse rate and prior cerebral magnetic resonance imaging activity. We did not find any evidence for the effect of age on the effectiveness of DMT. After inclusion of 1985 participants with progressive MS, the effect of DMT on disability mostly depended on MS phenotype, whereas its effect on relapses was driven mainly by prior relapse activity. CONCLUSIONS: DMT is generally most effective among patients with lower disability and in relapsing MS phenotypes. There is no evidence of attenuation of the effect of DMT with age.

Published
2023

4. Comparative effectiveness in multiple sclerosis: A methodological comparison

Author

Roos, I, Diouf, I, Sharmin, S, Horakova, D, Havrdova, EK, Patti, F, Shaygannejad, V, Ozakbas, S, Izquierdo, G, Eichau, S, Onofrj, M, Lugaresi, A, Alroughani, R, Prat, A, Girard, M, Duquette, P, Terzi, M, Boz, C, Grand'Maison, F, Sola, P, Ferraro, D, Grammond, P, Turkoglu, R, Buzzard, K, Skibina, O, Yamou, B, Altintas, A, Gerlach, O, van Pesch, V, Blanco, Y, Maimone, D, Lechner-Scott, J, Bergamaschi, R, Karabudak, R, McGuigan, C, Cartechini, E, Barnett, M, Hughes, S, Sa, MJ, Solaro, C, Ramo-Tello, C, Hodgkinson, S, Spitaleri, D, Soysal, A, Petersen, T, Granella, F, de Gans, K, McCombe, P, Ampapa, R, Van Wijmeersch, B, van der Walt, A, Butzkueven, H, Prevost, J, Sanchez-Menoyo, JL, Laureys, G, Gouider, R, Castillo-Trivino, T, Gray, O, Aguera-Morales, E, Al-Asmi, A, Shaw, C, Deri, N, Al-Harbi, T, Fragoso, Y, Csepany, T, Sempere, AP, Trevino-Frenk, I, Schepel, J, Moore, F, Malpas, C, Kalincik, T, Roos, I, Diouf, I, Sharmin, S, Horakova, D, Havrdova, EK, Patti, F, Shaygannejad, V, Ozakbas, S, Izquierdo, G, Eichau, S, Onofrj, M, Lugaresi, A, Alroughani, R, Prat, A, Girard, M, Duquette, P, Terzi, M, Boz, C, Grand'Maison, F, Sola, P, Ferraro, D, Grammond, P, Turkoglu, R, Buzzard, K, Skibina, O, Yamou, B, Altintas, A, Gerlach, O, van Pesch, V, Blanco, Y, Maimone, D, Lechner-Scott, J, Bergamaschi, R, Karabudak, R, McGuigan, C, Cartechini, E, Barnett, M, Hughes, S, Sa, MJ, Solaro, C, Ramo-Tello, C, Hodgkinson, S, Spitaleri, D, Soysal, A, Petersen, T, Granella, F, de Gans, K, McCombe, P, Ampapa, R, Van Wijmeersch, B, van der Walt, A, Butzkueven, H, Prevost, J, Sanchez-Menoyo, JL, Laureys, G, Gouider, R, Castillo-Trivino, T, Gray, O, Aguera-Morales, E, Al-Asmi, A, Shaw, C, Deri, N, Al-Harbi, T, Fragoso, Y, Csepany, T, Sempere, AP, Trevino-Frenk, I, Schepel, J, Moore, F, Malpas, C, and Kalincik, T

Abstract

BACKGROUND: In the absence of evidence from randomised controlled trials, observational data can be used to emulate clinical trials and guide clinical decisions. Observational studies are, however, susceptible to confounding and bias. Among the used techniques to reduce indication bias are propensity score matching and marginal structural models. OBJECTIVE: To use the comparative effectiveness of fingolimod vs natalizumab to compare the results obtained with propensity score matching and marginal structural models. METHODS: Patients with clinically isolated syndrome or relapsing remitting MS who were treated with either fingolimod or natalizumab were identified in the MSBase registry. Patients were propensity score matched, and inverse probability of treatment weighted at six monthly intervals, using the following variables: age, sex, disability, MS duration, MS course, prior relapses, and prior therapies. Studied outcomes were cumulative hazard of relapse, disability accumulation, and disability improvement. RESULTS: 4608 patients (1659 natalizumab, 2949 fingolimod) fulfilled inclusion criteria, and were propensity score matched or repeatedly reweighed with marginal structural models. Natalizumab treatment was associated with a lower probability of relapse (PS matching: HR 0.67 [95% CI 0.62-0.80]; marginal structural model: 0.71 [0.62-0.80]), and higher probability of disability improvement (PS matching: 1.21 [1.02 -1.43]; marginal structural model 1.43 1.19 -1.72]). There was no evidence of a difference in the magnitude of effect between the two methods. CONCLUSIONS: The relative effectiveness of two therapies can be efficiently compared by either marginal structural models or propensity score matching when applied in clearly defined clinical contexts and in sufficiently powered cohorts.

Published
2023

5. Early non-disabling relapses are important predictors of disability accumulation in people with relapsing-remitting multiple sclerosis

Author

Daruwalla, C, Shaygannejad, V, Ozakbas, S, Havrdova, EK, Horakova, D, Alroughani, R, Boz, C, Patti, F, Onofrj, M, Lugaresi, A, Eichau, S, Girard, M, Prat, A, Duquette, P, Yamout, B, Khoury, SJ, Sajedi, SA, Turkoglu, R, Altintas, A, Skibina, O, Buzzard, K, Grammond, P, Karabudak, R, van der Walt, A, Butzkueven, H, Maimone, D, Lechner-Scott, J, Soysal, A, John, N, Prevost, J, Spitaleri, D, Ramo-Tello, C, Gerlach, O, Iuliano, G, Foschi, M, Ampapa, R, van Pesch, V, Barnett, M, Shalaby, N, D'hooghe, M, Kuhle, J, Sa, MJ, Fabis-Pedrini, M, Kermode, A, Mrabet, S, Gouider, R, Hodgkinson, S, Laureys, G, Van Hijfte, L, Macdonell, R, Oreja-Guevara, C, Cristiano, E, McCombe, P, Sanchez-Menoyo, JL, Singhal, B, Blanco, Y, Hughes, S, Garber, J, Solaro, C, McGuigan, C, Taylor, B, de Gans, K, Habek, M, Al-Asmi, A, Mihaela, S, Castillo Trivino, T, Al-Harbi, T, Rojas, JI, Gray, O, Khurana, D, Van Wijmeersch, B, Grigoriadis, N, Inshasi, J, Oh, J, Aguera-Morales, E, Fragoso, Y, Moore, F, Shaw, C, Baghbanian, SM, Shuey, N, Willekens, B, Hardy, TA, Decoo, D, Sempere, AP, Field, D, Wynford-Thomas, R, Cunniffe, NG, Roos, I, Malpas, CB, Coles, AJ, Kalincik, T, Brown, JWL, MSBase, SG, Daruwalla, C, Shaygannejad, V, Ozakbas, S, Havrdova, EK, Horakova, D, Alroughani, R, Boz, C, Patti, F, Onofrj, M, Lugaresi, A, Eichau, S, Girard, M, Prat, A, Duquette, P, Yamout, B, Khoury, SJ, Sajedi, SA, Turkoglu, R, Altintas, A, Skibina, O, Buzzard, K, Grammond, P, Karabudak, R, van der Walt, A, Butzkueven, H, Maimone, D, Lechner-Scott, J, Soysal, A, John, N, Prevost, J, Spitaleri, D, Ramo-Tello, C, Gerlach, O, Iuliano, G, Foschi, M, Ampapa, R, van Pesch, V, Barnett, M, Shalaby, N, D'hooghe, M, Kuhle, J, Sa, MJ, Fabis-Pedrini, M, Kermode, A, Mrabet, S, Gouider, R, Hodgkinson, S, Laureys, G, Van Hijfte, L, Macdonell, R, Oreja-Guevara, C, Cristiano, E, McCombe, P, Sanchez-Menoyo, JL, Singhal, B, Blanco, Y, Hughes, S, Garber, J, Solaro, C, McGuigan, C, Taylor, B, de Gans, K, Habek, M, Al-Asmi, A, Mihaela, S, Castillo Trivino, T, Al-Harbi, T, Rojas, JI, Gray, O, Khurana, D, Van Wijmeersch, B, Grigoriadis, N, Inshasi, J, Oh, J, Aguera-Morales, E, Fragoso, Y, Moore, F, Shaw, C, Baghbanian, SM, Shuey, N, Willekens, B, Hardy, TA, Decoo, D, Sempere, AP, Field, D, Wynford-Thomas, R, Cunniffe, NG, Roos, I, Malpas, CB, Coles, AJ, Kalincik, T, Brown, JWL, and MSBase, SG

Abstract

BACKGROUND: The prognostic significance of non-disabling relapses in people with relapsing-remitting multiple sclerosis (RRMS) is unclear. OBJECTIVE: To determine whether early non-disabling relapses predict disability accumulation in RRMS. METHODS: We redefined mild relapses in MSBase as 'non-disabling', and moderate or severe relapses as 'disabling'. We used mixed-effects Cox models to compare 90-day confirmed disability accumulation events in people with exclusively non-disabling relapses within 2 years of RRMS diagnosis to those with no early relapses; and any early disabling relapses. Analyses were stratified by disease-modifying therapy (DMT) efficacy during follow-up. RESULTS: People who experienced non-disabling relapses within 2 years of RRMS diagnosis accumulated more disability than those with no early relapses if they were untreated (n = 285 vs 4717; hazard ratio (HR) = 1.29, 95% confidence interval (CI) = 1.00-1.68) or given platform DMTs (n = 1074 vs 7262; HR = 1.33, 95% CI = 1.15-1.54), but not if given high-efficacy DMTs (n = 572 vs 3534; HR = 0.90, 95% CI = 0.71-1.13) during follow-up. Differences in disability accumulation between those with early non-disabling relapses and those with early disabling relapses were not confirmed statistically. CONCLUSION: This study suggests that early non-disabling relapses are associated with a higher risk of disability accumulation than no early relapses in RRMS. This risk may be mitigated by high-efficacy DMTs. Therefore, non-disabling relapses should be considered when making treatment decisions.

Published
2023

6. Early non-disabling relapses are important predictors of disability accumulation in people with relapsing-remitting multiple sclerosis

Author

Altıntaş, Ayşe (ORCID 0000-0002-8524-5087 & YÖK ID 11611), Daruwalla, C.; Shaygannejad, V.; Ozakbas, S.; Havrdova, EK.; Horakova, D.; Alroughani, R.; Boz, C.; Patti, F.; Onofrj, M.; Lugaresi, A.; Eichau, S.; Girard, M.; Prat, A.; Duquette, P.; Yamout, B.; Khoury, S.J.; Sajedi, S.A.; Turkoglu, R.; Skibina, O.; Buzzard, K.; Grammond, P.; Karabudak, R.; van der Walt, A.; Butzkueven, H.; Maimone, D.; Lechner-Scott, J.; Soysal, A.; John, N.; Prevost, J.; Spitaleri, D.; Ramo-Tello, C.; Gerlach, O.; Iuliano, G.; Foschi, M.; Ampapa, R.; van Pesch, V.; Barnett, M.; Shalaby, N.; D'hooghe, M.; Kuhle, J.; Sa, M.J.; Fabis-Pedrini, M.; Kermode, A.; Mrabet, S.; Gouider, R.; Hodgkinson, S.; Laureys, G.; Van Hijfte, L.; Macdonell, R.; Oreja-Guevara, C.; Cristiano, E.; McCombe, P.; Sanchez-Menoyo, J.L.; Singhal, B.; Blanco, Y.; Hughes, S.; Garber, J.; Solaro, C.; McGuigan, C.; Taylor, B.; de Gans, K.; Habek, M.; Al-Asmi, A.; Mihaela, S.; Castillo Triviño, T.; Al-Harbi, T.; Rojas, J.I.; Gray, O.; Khuran,a D.; Van Wijmeersch, B.; Grigoriadis, N.; Inshasi, J.; Oh, J.; Aguera-Morales, E.; Fragoso, Y.; Moore, F.; Shaw, C.; Baghbanian, S.M.; Shuey, N.; Willekens, B.; Hardy, T.A.; Decoo, D.; Sempere, A.P.; Field, D.; Wynford-Thomas, R.; Cunniffe, NG.; Roos, I.; Malpas, C.B.; Coles, A.J.; Kalincik, T.; Brown, J.W.L., Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine, Altıntaş, Ayşe (ORCID 0000-0002-8524-5087 & YÖK ID 11611), Daruwalla, C.; Shaygannejad, V.; Ozakbas, S.; Havrdova, EK.; Horakova, D.; Alroughani, R.; Boz, C.; Patti, F.; Onofrj, M.; Lugaresi, A.; Eichau, S.; Girard, M.; Prat, A.; Duquette, P.; Yamout, B.; Khoury, S.J.; Sajedi, S.A.; Turkoglu, R.; Skibina, O.; Buzzard, K.; Grammond, P.; Karabudak, R.; van der Walt, A.; Butzkueven, H.; Maimone, D.; Lechner-Scott, J.; Soysal, A.; John, N.; Prevost, J.; Spitaleri, D.; Ramo-Tello, C.; Gerlach, O.; Iuliano, G.; Foschi, M.; Ampapa, R.; van Pesch, V.; Barnett, M.; Shalaby, N.; D'hooghe, M.; Kuhle, J.; Sa, M.J.; Fabis-Pedrini, M.; Kermode, A.; Mrabet, S.; Gouider, R.; Hodgkinson, S.; Laureys, G.; Van Hijfte, L.; Macdonell, R.; Oreja-Guevara, C.; Cristiano, E.; McCombe, P.; Sanchez-Menoyo, J.L.; Singhal, B.; Blanco, Y.; Hughes, S.; Garber, J.; Solaro, C.; McGuigan, C.; Taylor, B.; de Gans, K.; Habek, M.; Al-Asmi, A.; Mihaela, S.; Castillo Triviño, T.; Al-Harbi, T.; Rojas, J.I.; Gray, O.; Khuran,a D.; Van Wijmeersch, B.; Grigoriadis, N.; Inshasi, J.; Oh, J.; Aguera-Morales, E.; Fragoso, Y.; Moore, F.; Shaw, C.; Baghbanian, S.M.; Shuey, N.; Willekens, B.; Hardy, T.A.; Decoo, D.; Sempere, A.P.; Field, D.; Wynford-Thomas, R.; Cunniffe, NG.; Roos, I.; Malpas, C.B.; Coles, A.J.; Kalincik, T.; Brown, J.W.L., Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), and School of Medicine

Abstract

Background: the prognostic significance of non-disabling relapses in people with relapsing-remitting multiple sclerosis (RRMS) is unclear. Objective: to determine whether early non-disabling relapses predict disability accumulation in RRMS. Methods: we redefined mild relapses in MSBase as 'non-disabling', and moderate or severe relapses as 'disabling'. We used mixed-effects Cox models to compare 90-day confirmed disability accumulation events in people with exclusively non-disabling relapses within 2 years of RRMS diagnosis to those with no early relapses; and any early disabling relapses. Analyses were stratified by disease-modifying therapy (DMT) efficacy during follow-up. Results: people who experienced non-disabling relapses within 2 years of RRMS diagnosis accumulated more disability than those with no early relapses if they were untreated (n = 285 vs 4717; hazard ratio (HR) = 1.29, 95% confidence interval (CI) = 1.00-1.68) or given platform DMTs (n = 1074 vs 7262; HR = 1.33, 95% CI = 1.15-1.54), but not if given high-efficacy DMTs (n = 572 vs 3534; HR = 0.90, 95% CI = 0.71-1.13) during follow-up. Differences in disability accumulation between those with early non-disabling relapses and those with early disabling relapses were not confirmed statistically. Conclusion: this study suggests that early non-disabling relapses are associated with a higher risk of disability accumulation than no early relapses in RRMS. This risk may be mitigated by high-efficacy DMTs. Therefore, non-disabling relapses should be considered when making treatment decisions., The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was financially supported by National Health and Medical Research Council of Australia (fellowship nos.1140766 and 1080518, project grant nos. 1129189 and 1083539), the University of Melbourne (Faculty of Medicine, Dentistry and Health Sciences research fellowship), National Institute for Health and Care Research (UK) Advanced Fellowship (grant no. 301728; recipient JWLB) and Academic Clinical Fellowship (grant no. EAN/ACA-006/7488627/C; recipient CD). The MSBase Foundation is a not-for-profit organization that receives support from Roche, Merck, Biogen, Novartis, Bayer Schering, Sanofi Genzyme, and Teva. Role of the Funder/Sponsor: The National Health and Medical Research Council of Australia, the University of Melbourne and the National Institute for Health and Care Research (UK) had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Published
2023

9. Real-world experience with ocrelizumab in primary Progressive multiple sclerosis: Insights from the MSOCR-P cohort, a MSBase Registry sub-study

Author

Terzi, M., Rojas, J. I., Barnett, M., Fragoso, Y., Cartechini, E., Pucci, E., Willekens, B., Butler, E., Blanco, Y., Grigoriadis, N., Van Hijfte, L., Dirks, P., Liu, C., Rouzic, E. Muros-Le, Butzkueven, H., Al-Harbi, T., Laureys, G., Ozakbas, S., Spelman, T., Alroughani, R., Menoyo, J. L. Sanchez, Van Pesch, V., Kalincik, T., Lechner-Scott, J., Van der Walt, A., Grand'Maison, F., Boz, C., Buzzard, K., and Skibina, O.

Published
2022

11. Early non-disabling relapses are associated with a higher risk of disability accumulation in people with relapsing-remitting multiple sclerosis

Author

Coles, A., Daruwalla, C., Shaygannejad, V., Ozakbas, S., Havrdova, E. K., Alroughani, R., Patti, F., Onofrj, M., Eichau, S., Girard, M., Grand'Maison, F., Yamout, B., Sajedi, S. A., Amato, M. P., Altintas, A., Skibina, O., Grammond, P., Butzkueven, H., Maimone, D., Lechner-Scott, J., Soysal, A., John, N., Gerlach, O., Iuliano, G., Foschi, M., Van Pesch, V., Cartechini, E., Kuhle, J., Sa, M. J., Kermode, A., Gouider, R., Hodgkinson, S., McCombe, P., Sanchez-Menoyo, J. L., Singhal, B., Blanco, Y., Hughes, S., McGuigan, C., Taylor, B., Habek, M., Al-Asmi, A., Mihaela, S., Castillo Trivino, T., Al-Harbi, T., Rojas, J. I., Gray, O., Khurana, D., Van Wijmeersch, B., Kalincik, T., and Brown, J. W. L.

Published
2022

13. Confirmed disability progression as a marker of permanent disability in multiple sclerosis.

Author

Sharmin S., Bovis F., Malpas C., Horakova D., Havrdova E., Izquierdo G., Eichau S., Trojano M., Prat A., Girard M., Duquette P., Onofrj M., Lugaresi A., Grand'Maison F., Grammond P., Sola P., Ferraro D., Terzi M., Gerlach O., Alroughani R., Boz C., Shaygannejad V., van Pesch V., Cartechini E., Kappos L., Lechner-Scott J., Bergamaschi R., Turkoglu R., Solaro C., Iuliano G., Granella F., Van Wijmeersch B., Spitaleri D., Slee M., McCombe P., Prevost J., Ampapa R., Ozakbas S., Sanchez-Menoyo J., Soysal A., Vucic S., Petersen T., de Gans K., Butler E., Hodgkinson S., Sidhom Y., Gouider R., Cristiano E., Castillo-Trivino T., Saladino M., Barnett M., Moore F., Rozsa C., Yamout B., Skibina O., van der Walt A., Buzzard K., Gray O., Hughes S., Sempere A.P., Singhal B., Fragoso Y., Shaw C., Kermode A., Taylor B., Simo M., Shuey N., Al-Harbi T., Macdonell R., Dominguez J.A., Csepany T., Sirbu C., Sormani M.P., Butzkueven H., Kalincik T., Sharmin S., Bovis F., Malpas C., Horakova D., Havrdova E., Izquierdo G., Eichau S., Trojano M., Prat A., Girard M., Duquette P., Onofrj M., Lugaresi A., Grand'Maison F., Grammond P., Sola P., Ferraro D., Terzi M., Gerlach O., Alroughani R., Boz C., Shaygannejad V., van Pesch V., Cartechini E., Kappos L., Lechner-Scott J., Bergamaschi R., Turkoglu R., Solaro C., Iuliano G., Granella F., Van Wijmeersch B., Spitaleri D., Slee M., McCombe P., Prevost J., Ampapa R., Ozakbas S., Sanchez-Menoyo J., Soysal A., Vucic S., Petersen T., de Gans K., Butler E., Hodgkinson S., Sidhom Y., Gouider R., Cristiano E., Castillo-Trivino T., Saladino M., Barnett M., Moore F., Rozsa C., Yamout B., Skibina O., van der Walt A., Buzzard K., Gray O., Hughes S., Sempere A.P., Singhal B., Fragoso Y., Shaw C., Kermode A., Taylor B., Simo M., Shuey N., Al-Harbi T., Macdonell R., Dominguez J.A., Csepany T., Sirbu C., Sormani M.P., Butzkueven H., and Kalincik T.

Abstract

Background and purpose: The prevention of disability over the long term is the main treatment goal in multiple sclerosis (MS); however, randomized clinical trials evaluate only short-term treatment effects on disability. This study aimed to define criteria for 6-month confirmed disability progression events of MS with a high probability of resulting in sustained long-term disability worsening. Method(s): In total, 14,802 6-month confirmed disability progression events were identified in 8741 patients from the global MSBase registry. For each 6-month confirmed progression event (13,321 in the development and 1481 in the validation cohort), a sustained progression score was calculated based on the demographic and clinical characteristics at the time of progression that were predictive of long-term disability worsening. The score was externally validated in the Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) trial. Result(s): The score was based on age, sex, MS phenotype, relapse activity, disability score and its change from baseline, number of affected functional system domains and worsening in six of the domains. In the internal validation cohort, a 61% lower chance of improvement was estimated with each unit increase in the score (hazard ratio 0.39, 95% confidence interval 0.29-0.52; discriminatory index 0.89). The proportions of progression events sustained at 5 years stratified by the score were 1: 72%; 2: 88%; 3: 94%; 4: 100%. The results of the CLARITY trial were confirmed for reduction of disability progression that was >88% likely to be sustained (events with score >1.5). Conclusion(s): Clinicodemographic characteristics of 6-month confirmed disability progression events identify those at high risk of sustained long-term disability. This knowledge will allow future trials to better assess the effect of therapy on long-term disability accrual.Copyright © 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behal

Published
2022

14. Confirmed disability progression as a marker of permanent disability in multiple sclerosis

Author

Sharmin, S., Bovis, F., Malpas, C., Horakova, D., Havrdova, E.K., Izquierdo, G., Eichau, S., Trojano, M., Prat, A., Girard, M., Duquette, P., Onofrj, M., Lugaresi, A., Grand'Maison, F., Grammond, P., Sola, P., Ferraro, D., Terzi, M., Gerlach, O., Alroughani, R., Boz, C., Shaygannejad, V., van Pesch, V., Cartechini, E., Kappos, L., Lechner‐Scott, J., Bergamaschi, R., Turkoglu, R., Solaro, C., Iuliano, G., Granella, F., Van Wijmeersch, B., Spitaleri, D., Slee, M., McCombe, P., Prevost, J., Ampapa, R., Ozakbas, S., Sanchez‐Menoyo, J.L., Soysal, A., Vucic, S., Petersen, T., de Gans, K., Butler, E., Hodgkinson, S., Sidhom, Y., Gouider, R., Cristiano, E., Castillo‐Triviño, T., Saladino, M.L., Barnett, M., Moore, F., Rozsa, C., Yamout, B., Skibina, O., van der Walt, A., Buzzard, K., Gray, O., Hughes, S., Sempere, A.P., Singhal, B., Fragoso, Y., Shaw, C., Kermode, A., Taylor, B., Simo, M., Shuey, N., Al‐Harbi, T., Macdonell, R., Dominguez, J.A., Csepany, T., Sirbu, C.A., Sormani, M.P., Butzkueven, H., Kalincik, T., Sharmin, S., Bovis, F., Malpas, C., Horakova, D., Havrdova, E.K., Izquierdo, G., Eichau, S., Trojano, M., Prat, A., Girard, M., Duquette, P., Onofrj, M., Lugaresi, A., Grand'Maison, F., Grammond, P., Sola, P., Ferraro, D., Terzi, M., Gerlach, O., Alroughani, R., Boz, C., Shaygannejad, V., van Pesch, V., Cartechini, E., Kappos, L., Lechner‐Scott, J., Bergamaschi, R., Turkoglu, R., Solaro, C., Iuliano, G., Granella, F., Van Wijmeersch, B., Spitaleri, D., Slee, M., McCombe, P., Prevost, J., Ampapa, R., Ozakbas, S., Sanchez‐Menoyo, J.L., Soysal, A., Vucic, S., Petersen, T., de Gans, K., Butler, E., Hodgkinson, S., Sidhom, Y., Gouider, R., Cristiano, E., Castillo‐Triviño, T., Saladino, M.L., Barnett, M., Moore, F., Rozsa, C., Yamout, B., Skibina, O., van der Walt, A., Buzzard, K., Gray, O., Hughes, S., Sempere, A.P., Singhal, B., Fragoso, Y., Shaw, C., Kermode, A., Taylor, B., Simo, M., Shuey, N., Al‐Harbi, T., Macdonell, R., Dominguez, J.A., Csepany, T., Sirbu, C.A., Sormani, M.P., Butzkueven, H., and Kalincik, T.

Abstract

Background and purpose The prevention of disability over the long term is the main treatment goal in multiple sclerosis (MS); however, randomized clinical trials evaluate only short-term treatment effects on disability. This study aimed to define criteria for 6-month confirmed disability progression events of MS with a high probability of resulting in sustained long-term disability worsening. Methods In total, 14,802 6-month confirmed disability progression events were identified in 8741 patients from the global MSBase registry. For each 6-month confirmed progression event (13,321 in the development and 1481 in the validation cohort), a sustained progression score was calculated based on the demographic and clinical characteristics at the time of progression that were predictive of long-term disability worsening. The score was externally validated in the Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) trial. Results The score was based on age, sex, MS phenotype, relapse activity, disability score and its change from baseline, number of affected functional system domains and worsening in six of the domains. In the internal validation cohort, a 61% lower chance of improvement was estimated with each unit increase in the score (hazard ratio 0.39, 95% confidence interval 0.29–0.52; discriminatory index 0.89). The proportions of progression events sustained at 5 years stratified by the score were 1: 72%; 2: 88%; 3: 94%; 4: 100%. The results of the CLARITY trial were confirmed for reduction of disability progression that was >88% likely to be sustained (events with score ˃1.5). Conclusions Clinicodemographic characteristics of 6-month confirmed disability progression events identify those at high risk of sustained long-term disability. This knowledge will allow future trials to better assess the effect of therapy on long-term disability accrual.

Published
2022

20. Variability of the response to immunotherapy among subgroups of patients with multiple sclerosis.

Author

Van Pesch V., Eichau S., Zakaria M., Onofrj M., Lugaresi A., Alroughani R., Prat A., Girard M., Duquette P., Terzi M., Boz C., Grand'Maison F., Hamdy S., Sola P., Ferraro D., Grammond P., Turkoglu R., Butzkueven H., Yamout B., Altintas A., Maimone D., Lechner-Scott J., Bergamaschi R., Karabudak R., Giuliano F., Mcguigan C., Cartechini E., Barnett M., Hughes S., Sa M., Kappos L., Ramo-Tello C., Cristiano E., Hodgkinson S., Spitaleri D., Soysal A., Petersen T., Slee M., Butler E., Granella F., Verheul F., Mccombe P., Ampapa R., Skibina O., Prevost J., Sinnige L.G.F., Sanchez-Menoyo J.L., Vucic S., Laureys G., Van Hijfte L., Khurana D., Macdonell R., Castillo-Trivino T., Gray O., Aguera E., Kister I., Shaw C., Deri N., Al-Harbi T., Fragoso Y., Csepany T., Sempere A., Kalincik T., Diouf I., Malpas C., Horakova D., Kubala Havrdova E., Patti F., Shaygannejad V., Ozakbas S., Izquierdo G., Van Pesch V., Eichau S., Zakaria M., Onofrj M., Lugaresi A., Alroughani R., Prat A., Girard M., Duquette P., Terzi M., Boz C., Grand'Maison F., Hamdy S., Sola P., Ferraro D., Grammond P., Turkoglu R., Butzkueven H., Yamout B., Altintas A., Maimone D., Lechner-Scott J., Bergamaschi R., Karabudak R., Giuliano F., Mcguigan C., Cartechini E., Barnett M., Hughes S., Sa M., Kappos L., Ramo-Tello C., Cristiano E., Hodgkinson S., Spitaleri D., Soysal A., Petersen T., Slee M., Butler E., Granella F., Verheul F., Mccombe P., Ampapa R., Skibina O., Prevost J., Sinnige L.G.F., Sanchez-Menoyo J.L., Vucic S., Laureys G., Van Hijfte L., Khurana D., Macdonell R., Castillo-Trivino T., Gray O., Aguera E., Kister I., Shaw C., Deri N., Al-Harbi T., Fragoso Y., Csepany T., Sempere A., Kalincik T., Diouf I., Malpas C., Horakova D., Kubala Havrdova E., Patti F., Shaygannejad V., Ozakbas S., and Izquierdo G.

Abstract

Background: Our current understanding of demographic and clinical modifiers of the effectiveness of multiple sclerosis (MS) therapies is limited. Objective(s): To assess whether patients' response to disease modifying therapies (DMT) in MS varies by disease activity (annualised relapse rate, presence of new MRI lesions), disability, age, MS duration or disease phenotype. Method(s): Using the international MSBase registry, we selected patients with MS followed for >=1 year, with >=3 visits, >=1 visit per year. Marginal structural models (MSMs) were used to compare the hazard ratios (HR) of 6-month confirmed worsening and improvement of disability (EDSS), and the incidence of relapses between treated and untreated periods. MSMs were continuously re-adjusted for patient age, sex, pregnancy, date, time from first symptom, prior relapse history, disability and MRI activity. Result(s): Among 23 687 patients with relapsing MS, those on DMT experienced 20% greater chance of disability improvement [HR 1.20 (95% CI 1.0-1.5)], 47% lower risk of disability worsening [HR 0.53 (0.39-0.71)] and 51% reduction in relapses [HR 0.49 (0.43-0.55)]. The effect of DMT on relapses and EDSS worsening was attenuated with longer MS duration and higher prior relapse rate. The effect of DMT on EDSS improvement and relapses was more evident in low EDSS categories. DMT was associated with 51% EDSS improvement in patients without new MRI lesions [HR 1.51 (1.00-2.28)] compared to 4% in those with MRI activity [HR 1.04 (0.88-1.24)]. Among 26329 participants with relapsing or progressive MS, DMT was associated with 25% reduction in EDSS worsening and 42% reduction in relapses in patients with relapsing MS [HR 0.75 (0.65-0.86) and HR 0.58 (CI 0.54-62), respectively], while evidence for such beneficial effects of treatment in patients with progressive MS was not found [HR 1.11 (0.91-1.46) and HR 1.16 (0.91-1.46), respectively]. Conclusion(s): DMTs are associated with reduction in relapse frequency, pro

Published
2021

21. Variability of the Response to Immunotherapy among Sub-groups of Patients with Multiple Sclerosis.

Author

Diouf I., Malpas C., Horakova D., Havrdova E., Patti F., Shaygannejad V., Ozakbas S., Ayuso G.I., Madueno S.E., Zakaria M., Onofrj M., Lugaresi A., Alroughani R., Prat A., Girard M., Duquette P., Terzi M., Cavit B., GrandaMaison F., Hamdy S., Sola P., Ferraro D., Grammond P., Turkoglu R., Butzkueven H., Yamout B., Altintas A., VanPesch V., Maimone D., Lechner-Scott J., Bergamaschi R., Karabudak R., Iuliano G., McGuigan C., Cartechini E., Barnett M., Hughes S., Sa M.J., Kappos L., Ramo-Tello C., Cristiano E., Hodgkinson S., Spitaleri D.L.A., Soysal A., Petersen T., Slee M., Butler E., Granella F., Verheul F., McCombe P., Ampapa R., Skibina O., Prevost J., Sinnige L., Sanchez-Menoyo J.L., Vucic S., Laureys G., VanHijfte L., Khurana D., MacDonell R., Castillo-Trivino T., Gray O., Aguera-Morales E., Kister I., Shaw C., Deri N., Al-Harbi T., Fragoso Y., Csepany T., Sempere A., Kalincik T., Diouf I., Malpas C., Horakova D., Havrdova E., Patti F., Shaygannejad V., Ozakbas S., Ayuso G.I., Madueno S.E., Zakaria M., Onofrj M., Lugaresi A., Alroughani R., Prat A., Girard M., Duquette P., Terzi M., Cavit B., GrandaMaison F., Hamdy S., Sola P., Ferraro D., Grammond P., Turkoglu R., Butzkueven H., Yamout B., Altintas A., VanPesch V., Maimone D., Lechner-Scott J., Bergamaschi R., Karabudak R., Iuliano G., McGuigan C., Cartechini E., Barnett M., Hughes S., Sa M.J., Kappos L., Ramo-Tello C., Cristiano E., Hodgkinson S., Spitaleri D.L.A., Soysal A., Petersen T., Slee M., Butler E., Granella F., Verheul F., McCombe P., Ampapa R., Skibina O., Prevost J., Sinnige L., Sanchez-Menoyo J.L., Vucic S., Laureys G., VanHijfte L., Khurana D., MacDonell R., Castillo-Trivino T., Gray O., Aguera-Morales E., Kister I., Shaw C., Deri N., Al-Harbi T., Fragoso Y., Csepany T., Sempere A., and Kalincik T.

Abstract

Objective: To assess whether patients' response to disease modifying therapies (DMT) in multiple sclerosis (MS) varies by disease activity (annualised relapse rate, presence of new MRI lesions), disability, age, MS duration or disease phenotype. Background(s): Our understanding of demographic and clinical modifiers of the effectiveness of MS therapies is limited. Design/Methods: Using the international MSBase registry, we selected patients with MS followed for >=1 year, with >=3 visits, >=1 visit per year. Marginal structural models were used to compare the hazard ratios (HR) of 6-month confirmed worsening and improvement of disability (EDSS), and the incidence of relapses between treated and untreated periods. Models were continuously re-adjusted for patient age, sex, pregnancy, date, time from first symptom, prior relapse history, disability and MRI activity. Result(s): Among 23687 patients with relapsing MS, those on DMTs experienced 48% reduction in relapse incidence [HR=0.52 (0.44-0.61)], 48% lower risk of disability worsening [HR=0.52 (0.38-0.71)] and 33% greater chance of disability improvement [HR=1.33 (95%CI 1.0-1.5)]. The effect of DMTs on EDSS worsening and improvement and the risk of relapses was attenuated with more severe disability. The effect of DMTs on reducing relapses declined with higher prior relapse rate and in patients with prior cerebral MRI activity. Among 26329 participants with relapsing or progressive MS, DMTs were associated with 25% reduction in EDSS worsening and 42% reduction in relapses in patients with relapsing MS [HR=0.75 (0.65-0.86) and HR=0.58 (0.54-62), respectively], while evidence for such beneficial effects of treatment in patients with progressive MS was not found [HR=1.11 (0.91-1.46) and HR=1.16 (0.91-1.46), respectively]. Conclusion(s): DMTs are associated with reduction in relapse frequency, progression of disability, and increased chance of recovery from disability. The DMTs are most effective among patients with lower

Published
2021

23. Predicting long-term sustained disability progression in multiple sclerosis.

Author

Van Wijmeersch B., Malpas C., Hupperts R.M.M., Alroughani R., Boz C., Shaygannejad V., Van Pesch V., Kappos L., Lechner-Scott J., Bergamaschi R., Turkoglu R., Solaro C., Ramo-Tello C., Iuliano G., Granella F., Spitaleri D.L.A., Bolanos R.F., Slee M., McCombe P., Prevost J., Ampapa R., Ozakbas S., Sanchez-Menoyo J.L., Soysal A., Vucic O., Petersen T., Verheul F., Butler E., Hodgkinson S., Sidhom Y., Gouider R., Cristiano E., Urtaza F.J.O., Saladino M.L., Barnett M., Deri N., Moore F., Rozsa C., Yamout B., Skibina O., Gray O., Campbell J., Sempere A., Singhal B., Fragoso Y., Shaw C., Kermode A., Petkovska-Boskova T., Taylor B., Simo M., Vella N., Shuey N., Alkhaboori J., Al-Harbi T., Macdonell R., Dominguez J.A., Kister I., Csepany T., Vrech C., Kovacs K., Sirbu C.A., Hughes S., Sormani M.P., Butzkueven H., Kalincik T., Sharmin S., Bovis F., Horakova D., Havrdova E., Ayuso G.I., Eichau S., Trojano M., Prat A., Girard M., Duquette P., Onofrj M., Lugaresi A., Grand'Maison F., Grammond P., Sola P., Ferraro D., Terzi M., Van Wijmeersch B., Malpas C., Hupperts R.M.M., Alroughani R., Boz C., Shaygannejad V., Van Pesch V., Kappos L., Lechner-Scott J., Bergamaschi R., Turkoglu R., Solaro C., Ramo-Tello C., Iuliano G., Granella F., Spitaleri D.L.A., Bolanos R.F., Slee M., McCombe P., Prevost J., Ampapa R., Ozakbas S., Sanchez-Menoyo J.L., Soysal A., Vucic O., Petersen T., Verheul F., Butler E., Hodgkinson S., Sidhom Y., Gouider R., Cristiano E., Urtaza F.J.O., Saladino M.L., Barnett M., Deri N., Moore F., Rozsa C., Yamout B., Skibina O., Gray O., Campbell J., Sempere A., Singhal B., Fragoso Y., Shaw C., Kermode A., Petkovska-Boskova T., Taylor B., Simo M., Vella N., Shuey N., Alkhaboori J., Al-Harbi T., Macdonell R., Dominguez J.A., Kister I., Csepany T., Vrech C., Kovacs K., Sirbu C.A., Hughes S., Sormani M.P., Butzkueven H., Kalincik T., Sharmin S., Bovis F., Horakova D., Havrdova E., Ayuso G.I., Eichau S., Trojano M., Prat A., Girard M., Duquette P., Onofrj M., Lugaresi A., Grand'Maison F., Grammond P., Sola P., Ferraro D., and Terzi M.

Abstract

Objective: Using global MSBase registry, this study establishes 6-month confirmed disability progression events as indicators of long-term disability worsening suitable for use in randomized clinical trials in multiple sclerosis (MS). Background(s): Randomized clinical trials evaluate short-term treatment effect on disability in the form of 3-6-month confirmed disability progression, but whether these translate into long-term disability outcomes is unknown. Design/Methods: A Cox proportional hazards model identified associations between patients' demographic and clinical characteristics and the probability of recovery from disability progression events. The coefficients from this model were used to calculate a sustained progression score, which was evaluated in a validation cohort and applied to a trial cohort. Result(s): 902 patients (development cohort), patient characteristics at the time of progression associated with lower probability of subsequent improvement were age (hazard ratio (HR)=0.98), primary progressive (HR=0.37) and progressive-relapsing (HR=0.36) MS, expanded disability status scale score >=6 (HR=0.71) and its change from baseline (HR=0.67), number of affected functional system scores (HR=0.92) and pyramidal (HR=0.79) functional system score (p<0.05). The strength of the association with pyramidal score decreased with time (HR=1.01). A relapse within previous month (HR=1.46) and worsening in sensory functional system score (HR=1.17) were associated with higher probability of improvement after progression. The sustained progression score (range 0.39-4.79) in the validation cohort with 1,271 progression events, estimated a 53% lower chance of improvement for each unit increase in the score (HR=0.47). The proportions of progression events sustained at 5 years stratified by the score were 1: 68%, 2: 79%, 3: 94%, 4: 100%. The progression scores were then applied to the CLARITY trial data. Conclusion(s): Estimate of the probability of disability progress

Published
2020

24. Distinct Cognitive Trajectories in Late Life and Associated Predictors and Outcomes: A Systematic Review

Author

Wu, Z, Phyo, AZZ, Al-Harbi, T, Woods, RL, Ryan, J, Wu, Z, Phyo, AZZ, Al-Harbi, T, Woods, RL, and Ryan, J

Abstract

BACKGROUND: Cognitive aging is a dynamic process in late life with significant heterogeneity across individuals. OBJECTIVE: To review the evidence for latent classes of cognitive trajectories and to identify the associated predictors and outcomes. METHODS: A systematic search was performed in MEDLINE and EMBASE for articles that identified two or more cognitive trajectories in adults. The study was conducted following the PRISMA statement. RESULTS: Thirty-seven studies were included, ranging from 219 to 9,704 participants, with a mean age of 60 to 93.4 years. Most studies (n = 30) identified distinct cognitive trajectories using latent class growth analysis. The trajectory profile commonly consisted of three to four classes with progressively decreasing baseline and increasing rate of decline-a 'stable-high' class characterized as maintenance of cognitive function at high level, a 'minor-decline' class or 'stable-medium' class that declines gradually over time, and a 'rapid-decline' class with the steepest downward slope. Generally, membership of better classes was predicted by younger age, being female, more years of education, better health, healthier lifestyle, higher social engagement and lack of genetic risk variants. Some factors (e.g., education) were found to be associated with cognitive function over time only within individual classes. CONCLUSION: Cognitive aging in late life is a dynamic process with significant inter-individual variability. However, it remains unclear whether similar patterns of cognitive aging are observed across all cognitive domains. Further research into unique factors which promote the maintenance of high-cognitive function is needed to help inform public policy.

Published
2020

34. Influence of aluminium concentration in Zn0:9V0:1O nanoparticles on structural and optical properties.

Author

Sayari, A., El Mir, L., Al-Heniti, S., Al-Harbi, T., Yaghmour, S. J., and Al-Ghamdi, A.A.

Subjects
ALUMINUM alloys, ZINC compounds, METAL microstructure, OPTICAL properties of metals, MECHANICAL properties of metals
Abstract

The (V,Al) co-doped ZnO nano-structured powders (Zn0.9-xV0.1AlxO, where x = 0.02, 0.03 and 0.04) were synthesized via the sol-gel technique and their structural and optical properties were investigated. The effect of Al concentration on the structural and optical properties of the Zn0.9-xV0.1AlxO nanopowders was studied using various techniques. The XRD patterns indicate that the samples have a polycrystalline wurtzite structure. The crystallite size increases with increasing the Al content and lies in the range of 23 to 30 nm. The lattice strain, estimated by the Stokes-Wilson equation, decreases when Al content increases. SEM and TEM micrographs show that Zn0.9-xV0.1AlxO powders are the agglomeration of nanoparticles having spherical and hexagonal shapes with dimensions ranging from 20 to 30 nm. FT-IR spectra show a distinct absorption peak at about 500 cm-1 for ZnO stretching modes and other peaks related to OH and H2O bands. Raman spectra confirm the wurtzite structure of the Zn0.9-xV0.1AlxO nanoparticles. The direct band gaps of the synthesized Zn0.9-xV0.1AlxO nanopowders, estimated from the Brus equation and the crystallite sizes deduced from XRD, are around 3.308 eV. The decomposition process of the dried gel system was investigated by thermal gravimetric analysis (TGA). [ABSTRACT FROM AUTHOR]

Published
2015
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35. Leading cause of death in comparison to COVID-19 in Saudi Arabia.

Author

Bashir, S., Altwaijri, N., Al-Harbi, T. M., and Abualait, T.

Abstract

The article discusses COVID-19 has reached a calamitous scale globally1; increasing the death tolls around the world, claiming over 2 million lives. Topics include a web-based national listing of hard-surface disinfectants and hand sanitizers; and 8.7% included quaternary ammonium compounds with other concomitant active agents.

Published
2021

36. The risk of relapse following on-treatment clinically silent lesions in patients with relapsing-remitting multiple sclerosis

Author

Brown, J. W. L., Lugaresi, A., Horakova, D., Havrdova, E., Jokubaitis, V., Lechner-Scott, J., Trojano, M., Min, M., Shaw, C., Shuey, N., Slee, M., Mccombe, P., Pesch, V., Wijmeersch, B., Prevost, J., Moore, F., Prat, A., Girard, M., Duquette, P., Ayrignac, X., Sempere, A. Perez, Sanchez-Menoyo, J. L., Cristina Ramo-Tello, Csepany, T., Hutchinson, M., Luca, G., Bergamaschi, R., Granella, F., Curti, E., Tsantes, E., Sola, P., Ferraro, D., Alroughani, R., Hupperts, R., Al-Harbi, T., Sidhom, Y., Boz, C., Terzi, M., Ozakbas, S., Soysal, A., Pucci, E., Izquierdo, G., Iuliano, G., Rio, M. Edite, Spitaleri, D., Grammond, P., Grand Maison, F., Butzkueven, H., and Kalincik, T.

39. Variability of the response to immunotherapy among subgroups of patients with multiple sclerosis

Author

Diouf, I, Malpas, C, Horakova, D, Havrdova, EK, Patti, F, Shaygannejad, V, Ozakbas, S, Izquierdo, G, Eichau, S, Zakaria, M, Onofrj, M, Lugaresi, A, Alroughani, R, Prat, A, Girard, M, Duquette, P, Terzi, M, Boz, C, Grand'Maison, F, Hamdy, S, Sola, P, Ferraro, D, Grammond, P, Turkoglu, R, Butzkueven, H, Yamout, B, Altintas, A, Van Pesch, V, Maimone, D, Lechner-Scott, J, Bergamaschi, R, Karabudak, R, Giuliano, F, Mcguigan, C, Cartechini, E, Barnett, M, Hughes, S, Sa, M, Kappos, L, Ramo-Tello, C, Cristiano, E, Hodgkinson, S, Spitaleri, D, Soysal, A, Petersen, T, Slee, M, Butler, E, Granella, F, Verheul, F, Mccombe, P, Ampapa, R, Skibina, O, Prevost, J, Sinnige, LGF, Sanchez-Menoyo, JL, Vucic, S, Laureys, G, Van Hijfte, L, Khurana, D, Macdonell, R, Castillo-Trivino, T, Gray, O, Aguera, E, Kister, I, Shaw, C, Deri, N, Al-Harbi, T, Fragoso, Y, Csepany, T, Sempere, A, and Kalincik, T

42. Redefining the Multiple Sclerosis Severity Score (MSSS): The effect of sex and onset phenotype

Author

Riadh Gouider, Talal Al-Harbi, Krisztian Kasa, Ingrid van der Mei, Carmen Adella Sirbu, Richard Roxburgh, Alessandra Lugaresi, Daniele Spitaleri, Karim Kotkata, Steve Simpson, Javier Olascoaga, Edgardo Cristiano, Raed Alroughani, Tomas Kalincik, Cameron Shaw, Attila Sas, Bruce V. Taylor, Jim Stankovich, Ayse Altintas, Bassem Yamout, Yuan Zhou, Suzi B. Claflin, José C. Álvarez-Cermeño, Tünde Csépány, José Luis Sánchez Menoyo, Guy Laureys, Danny Decoo, Helmut Butzkueven, Seyed Aidin Sajedi, Leigh Blizzard, Franco Granella, Christopher McGuigan, Yara Dadalti Fragoso, Jorge Millán-Pascual, Eugenio Pucci, Allan G. Kermode, Todd A. Hardy, Stella Hughes, Zhou Y., Claflin S.B., Stankovich J., van der Mei I., Simpson S., Roxburgh R.H., Kalincik T., Blizzard L., Lugaresi A., Alroughani R., Sajedi S.A., Butzkueven H., Pucci E., Spitaleri D.L.A., Granella F., Cristiano E., Yamout B., Hughes S., Gouider R., Sanchez Menoyo J.L., Olascoaga J., McGuigan C., Shaw C., Kermode A.G., Kasa K., Al-Harbi T., Altintas A., Laureys G., Fragoso Y., Hardy T.A., Csepany T., Sirbu C.-A., Decoo D., Sas A., Alvarez-Cermeno J.C., Kotkata K., Millan-Pascual J., and Taylor B.V.

Subjects
Male, medicine.medical_specialty, Multiple Sclerosis, Severity of Illness Index, Disability Evaluation, 03 medical and health sciences, 0302 clinical medicine, Recurrence, Internal medicine, medicine, Humans, Disability progression, Multiple sclerosi, 030304 developmental biology, 0303 health sciences, business.industry, Multiple sclerosis, onset phenotype, medicine.disease, Phenotype, Clinical neurology, disability progression, Neurology, Disease Progression, Female, Neurology (clinical), business, 030217 neurology & neurosurgery, Multiple Sclerosis Severity Score
Abstract

Background: The Multiple Sclerosis Severity Score (MSSS) is a widely used measure of the disability progression rate. However, the global MSSS may not be the best basis for comparison between all patient groups. Objective: We evaluated sex-specific and onset phenotype–specific MSSS matrices to determine if they were more effective than the global MSSS as a basis for comparison within these subsets. Methods: Using a large international dataset of multiple sclerosis (MS) patient records and the original MSSS algorithm, we constructed global, sex-specific and onset phenotype–specific MSSS matrices. We compared matrices using permutation analysis. Results: Our final dataset included 30,203 MS cases, with 28.9% males and 6.5% progressive-onset cases. Our global MSSS matrix did not differ from previously published data ( p > 0.05). The progressive-onset-specific matrix differed significantly from the relapsing-onset-specific matrix ( p Conclusion: The differences in the disability accrual rate between progressive- and relapsing-onset MS have a significant effect on MSSS. An onset-specific MSSS should be used when comparing the rate of disability progression among progressive-onset cases and for mixed cohorts.

Published
2020

43. Clinical and therapeutic predictors of disease outcomes in AQP4-IgG+ neuromyelitis optica spectrum disorder

Author

Guillermo Izquierdo, Ayse Altintas, Tomas Kalincik, Petra Nytrova, Charles B Malpas, Roberto Bergamaschi, Ilya Kister, Diana Ferraro, Aysun Soysal, Helmut Butzkueven, Sara Eichau, Francois Grand'Maison, Guy Laureys, Jeannette Lechner-Scott, Jyh Yung Hor, Pamela A. McCombe, Yara Dadalti Fragoso, Steve Vucic, Rana Karabudak, Raed Alroughani, Cavit Boz, Celia Oreja-Guevara, Eugenio Pucci, Tünde Csépány, Patrizia Sola, Serkan Ozakbas, Bhim Singhal, Francesco Patti, Maria Trojano, Franco Granella, Marco Onofrj, Alessandra Lugaresi, Recai Turkoglu, Mark Marriott, Murat Terzi, Amy Kunchok, Talal Al-Harbi, Magdolna Simó, Javier Olascoaga, Eva Havrdova, Bassem Yamout, Kunchok A., Malpas C., Nytrova P., Havrdova E.K., Alroughani R., Terzi M., Yamout B., Hor J.Y., Karabudak R., Boz C., Ozakbas S., Olascoaga J., Simo M., Granella F., Patti F., McCombe P., Csepany T., Singhal B., Bergamaschi R., Fragoso Y., Al-Harbi T., Turkoglu R., Lechner-Scott J., Laureys G., Oreja-Guevara C., Pucci E., Sola P., Ferraro D., Altintas A., Soysal A., Vucic S., Grand'Maison F., Izquierdo G., Eichau S., Lugaresi A., Onofrj M., Trojano M., Marriott M., Butzkueven H., Kister I., Kalincik T., and Ondokuz Mayıs Üniversitesi

Subjects
Male, Time Factors, Azathioprine, Severity of Illness Index, 0302 clinical medicine, Natalizumab, Recurrence, Outcome Assessment, Health Care, Disability, Immunosuppression, Neuromyelitis optica spectrum disorder, Predictors, Relapses, Therapy, 030212 general & internal medicine, Registries, Relapse, Hazard ratio, Neuromyelitis Optica, Age Factors, General Medicine, Middle Aged, Neurology, Cohort, Disease Progression, Female, Rituximab, medicine.drug, Cohort study, Adult, medicine.medical_specialty, 03 medical and health sciences, Internal medicine, medicine, Humans, Immunologic Factors, Aquaporin 4, Neuromyelitis optica, Expanded Disability Status Scale, Proportional hazards model, business.industry, Mycophenolic Acid, medicine.disease, Immunoglobulin G, Neurology (clinical), business, 030217 neurology & neurosurgery, Follow-Up Studies, Predictor
Abstract

Altintas, Ayse/0000-0002-8524-5087; Laureys, Guy/0000-0002-1708-4373; Vucic, Steve/0000-0002-8323-873X; patti, francesco/0000-0002-6923-0846; Kister, Ilya/0000-0003-3549-949X; Lugaresi, Alessandra/0000-0003-2902-5589 WOS: 000521648000049 PubMed: 31877445 Background: Aquaporin-4-IgG positive (AQP4-IgG(+)) Neuromyelitis Optica Spectrum Disorder (NMOSD) is an uncommon central nervous system autoimmune disorder. Disease outcomes in AQP4-IgG + NMOSD are typically measured by relapse rate and disability. Using the MSBase, a multi-centre international registry, we aimed to examine the impact immunosuppressive therapies and patient characteristics as predictors of disease outcome measures in AQP4-IgG + NMOSD. Method: This MSBase cohort study of AQP4-IgG + NMOSD patients examined modifiers of relapse in a multivariable proportional hazards model and expanded disability status score (EDSS) using a mixed effects model. Results: 206 AQP4-IgG + patients were included (median follow-up 3.7 years). Age (hazard ratio [HR] = 0.82 per decade, p = 0.001), brainstem onset (HR = 0.45, p = 0.009), azathioprine (HR = 0.46, p < 0.001) and mycophenolate mofetil (HR = 0.09, p = 0.012) were associated with a reduced risk of relapse. A greater EDSS was associated with age (beta = 0.45 (per decade), p < 0.001) and disease duration (beta = 0.07 per year, p < 0.001). A slower increase in EDSS was associated with azathioprine (beta = -0.48, p < 0.001), mycophenolate mofetil (beta = -0.69, p = 0.04) and rituximab (beta = -0.35, p = 0.024). Interpretation: This study has demonstrated that azathioprine and mycophenolate mofetil reduce the risk of relapses and disability progression is modified by azathioprine, mycophenolate mofetil and rituximab. Age and disease duration were the only patient characteristics that modified the risk of relapse and disability in our cohort. National Health and Medical Research Council of AustraliaNational Health and Medical Research Council of Australia [1083539, 1129189, 1140766, 1080518]; MerckMerck & Company; BiogenBiogen; NovartisNovartis; Bayer-ScheringBayer AG; Sanofi-Genzyme; Teva This study was financially supported by National Health and Medical Research Council of Australia [project grants 1083539 and 1129189, and fellowships 1140766 and 1080518]. The MSBase Foundation is a not-for-profit organization that receives support from Merck, Biogen, Novartis, Bayer-Schering, Sanofi-Genzyme and Teva. The study was conducted separately and apart from the guidance of the sponsors.

Published
2020

44. Risk of secondary progressive multiple sclerosis: A longitudinal study

Author

Michael Barnett, Bhim Singhal, Maria Trojano, Franco Granella, Neil Shuey, Guillermo Izquierdo, Dana Horakova, Helmut Butzkueven, Talal Al-Harbi, Maria Laura Saladino, Cameron Shaw, Adam Fambiatos, Bart Van Wijmeersch, Serkan Ozakbas, Tünde Csépány, Freek Verheul, Cavit Boz, Tim Spelman, Pierre Duquette, Jeannette Lechner-Scott, Bassem Yamout, Roberto Bergamaschi, Vincent Van Pesch, Claudio Solaro, Edgardo Cristiano, Patrizia Sola, Vilija Jokubaitis, Jae Kwan Jun, Alessandra Lugaresi, Javier Olascoaga, Aysun Soysal, Thor Petersen, Mark Slee, Raed Alroughani, Francois Grand'Maison, Orla Gray, Tomas Kalincik, Marc Girard, Gerardo Iuliano, Anneke van der Walt, Eva Havrdova, Jose Luis Sanchez-Menoyo, Radek Ampapa, Julie Prevost, Steve Vucic, Pamela A. McCombe, Recai Turkoglu, Yara Dadalti Fragoso, Jordana Hughes, Olga Skibina, Murat Terzi, Eugenio Pucci, Diana Ferraro, Pierre Grammond, Fraser Moore, Ayse Altintas, Suzanne Hodgkinson, Youssef Sidhom, Norma Deri, Alexandre Prat, Raymond Hupperts, Daniele Spitaleri, Bruce V. Taylor, Fambiatos A., Jokubaitis V., Horakova D., Kubala Havrdova E., Trojano M., Prat A., Girard M., Duquette P., Lugaresi A., Izquierdo G., Grand'Maison F., Grammond P., Sola P., Ferraro D., Alroughani R., Terzi M., Hupperts R., Boz C., Lechner-Scott J., Pucci E., Bergamaschi R., Van Pesch V., Ozakbas S., Granella F., Turkoglu R., Iuliano G., Spitaleri D., McCombe P., Solaro C., Slee M., Ampapa R., Soysal A., Petersen T., Sanchez-Menoyo J.L., Verheul F., Prevost J., Sidhom Y., Van Wijmeersch B., Vucic S., Cristiano E., Saladino M.L., Deri N., Barnett M., Olascoaga J., Moore F., Skibina O., Gray O., Fragoso Y., Yamout B., Shaw C., Singhal B., Shuey N., Hodgkinson S., Altintas A., Al-Harbi T., Csepany T., Taylor B., Hughes J., Jun J.-K., van der Walt A., Spelman T., Butzkueven H., Kalincik T., Ondokuz Mayıs Üniversitesi, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, and UCL - (SLuc) Service de neurologie

Subjects
Adult, Male, Risk, medicine.medical_specialty, Longitudinal study, Immunologic Factors, multiple sclerosis, Severity of Illness Index, 03 medical and health sciences, 0302 clinical medicine, Multiple Sclerosis, Relapsing-Remitting, disease modifying therapies, prognostics, Internal medicine, Severity of illness, Medicine, Humans, Longitudinal Studies, 030304 developmental biology, 0303 health sciences, business.industry, Multiple sclerosis, Disease progression, prediction, Multiple Sclerosis, Chronic Progressive, medicine.disease, SPMS, Clinical neurology, Natural history, Neurology, multiple sclerosi, disease modifying therapie, Disease Progression, Secondary progressive multiple sclerosis, Female, Neurology (clinical), business, prognostic, 030217 neurology & neurosurgery
Abstract

Turkoglu, Recai/0000-0001-9724-851X; Ferraro, Diana/0000-0003-4818-3806; McCombe, Pamela/0000-0003-2704-8517; Altintas, Ayse/0000-0002-8524-5087; Jokubaitis, Vilija G./0000-0002-3942-4340; Slee, Mark/0000-0003-4323-2453; Lugaresi, Alessandra/0000-0003-2902-5589; van Pesch, Vincent/0000-0003-2885-9004; Vucic, Steve/0000-0002-8323-873X WOS: 000481049900001 PubMed: 31397221 Background: The risk factors for conversion from relapsing-remitting to secondary progressive multiple sclerosis remain highly contested. Objective: The aim of this study was to determine the demographic, clinical and paraclinical features that influence the risk of conversion to secondary progressive multiple sclerosis. Methods: Patients with adult-onset relapsing-remitting multiple sclerosis and at least four recorded disability scores were selected from MSBase, a global observational cohort. The risk of conversion to objectively defined secondary progressive multiple sclerosis was evaluated at multiple time points per patient using multivariable marginal Cox regression models. Sensitivity analyses were performed. Results: A total of 15,717 patients were included in the primary analysis. Older age (hazard ratio (HR) = 1.02, p < 0.001), longer disease duration (HR = 1.01, p = 0.038), a higher Expanded Disability Status Scale score (HR = 1.30, p < 0.001), more rapid disability trajectory (HR = 2.82, p < 0.001) and greater number of relapses in the previous year (HR = 1.07, p = 0.010) were independently associated with an increased risk of secondary progressive multiple sclerosis. Improving disability (HR = 0.62, p = 0.039) and disease-modifying therapy exposure (HR = 0.71, p = 0.007) were associated with a lower risk. Recent cerebral magnetic resonance imaging activity, evidence of spinal cord lesions and oligoclonal bands in the cerebrospinal fluid were not associated with the risk of conversion. Conclusion: Risk of secondary progressive multiple sclerosis increases with age, duration of illness and worsening disability and decreases with improving disability. Therapy may delay the onset of secondary progression. National Health and Medical Research Council of AustraliaNational Health and Medical Research Council of Australia [1083539, 1129189, 1140766]; BiogenBiogen; RocheRoche Holding; Bayer ScheringBayer AG; Sanofi Genzyme; Teva; MerckMerck & Company; NovartisNovartis The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was financially supported by National Health and Medical Research Council of Australia (project grants 1083539 and 1129189 and fellowship 1140766). The MSBase Foundation is a not-for-profit organisation that receives support from Merck, Biogen, Roche, Novartis, Bayer Schering, Sanofi Genzyme and Teva. The study was conducted separately and apart from the guidance of the sponsors.

Published
2020
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45. The impact of COVID-19 infection on multiple sclerosis disease course across 12 countries: a propensity-score-matched cohort study.

Author

Levitz D, Chao Foong Y, Sanfilippo P, Spelman T, Rath L, Roldan A, Lal A, Monif M, Jokubaitis V, Ozakbas S, Alroughani R, Boz C, Terzi M, Kalincik T, Blanco Y, Foschi M, Surcinelli A, Buzzard K, Skibina O, Laureys G, Van Hijfte L, Ramo-Tello C, Soysal A, Sanchez-Menoyo JL, Habek M, Cartechini E, Rojas JI, Karabudak R, Willekens B, Al-Harbi T, Fragoso Y, Castillo-Triviño T, Decoo D, Aragon de Vecino MC, Skromne E, Sirbu CA, Zhu C, Merlo D, Gresle M, Butzkueven H, and Van Der Walt A

Abstract

Background: The relationship between coronavirus disease 2019 (COVID-19) infection and multiple sclerosis (MS) relapse and disease progression remains unclear. Previous studies are limited by small sample sizes and most lack a propensity-matched control cohort., Objective: To evaluate the effect of COVID-19 infection on MS disease course with a large propensity-matched cohort., Design: This multi-centre cohort study analysed relapse and disability outcomes post-COVID-19 infection after balancing covariates using a propensity score matching method. The study period was from the 11th of September 2019 to the 16th of February 2023. The mean follow-up period was 1.7 years., Methods: Data were retrieved from the MSBase Registry. Propensity scores were obtained based on age, sex, disease duration, baseline Expanded Disability Status Scale (EDSS), MS course, relapses pre-baseline, disease-modifying therapy (DMT) class and country. Primary outcomes were time to first relapse, annualised relapse rate (ARR) and time to confirm EDSS progression. Secondary outcomes were time to EDSS of 3, 4 or 6. Sensitivity analyses with baseline DMT classes were performed., Results: The study included 2253 cases and 6441 controls. After matching, there were 2161 cases and an equal number of matched controls. Cases had a significantly higher ARR (ARR = 0.10 [95% CI 0.09-0.11]) compared to controls (ARR = 0.07 [95% CI 0.06-0.08]). Cases had a significantly greater hazard of time to first relapse compared to controls (hazard ratio (HR) = 1.54 [95% CI 1.29-1.84]). There was no association between COVID-19 infection and 24-week EDSS progression (HR = 1.18 [95% CI 0.92-1.52]), or time to EDSS of 3, 4 or 6. For patients on interferons and glatiramer acetate (BRACE), COVID-19 infection was associated with a greater hazard of time to first relapse (HR = 1.83 [95% CI 1.25-2.68]) and greater hazard of time to EDSS of 3 (HR = 2.04 [95% CI 1.06-3.90]) compared to patients on BRACE therapy without COVID-19 infection., Conclusion: COVID-19 infection was associated with a significantly increased MS relapse rate and a shorter time to first relapse. There was no effect on confirmed EDSS progression over the short term. These results support ongoing COVID-19 risk minimisation strategies to protect patients with MS., (© The Author(s), 2024.)

Published
2024
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46. Exploring COVID-19 vaccine adverse events among pregnant women: a cross-sectional study, 2022.

Author

Amer AA, Amer SA, Badokhon A, Hammad SM, Wasfy MA, Khan M, Ateyah Al-Harbi T, Alobaid SQ, Eskander G, Abdel-Azeem A, Alshowair A, and Ramadan MS

Abstract

Background: Clear and trustworthy information is crucial to improving public acceptance of COVID-19 vaccinations, especially among pregnant women. Given the increased risk of severe viral pneumonia in pregnant women, it is critical to foster confidence in the vaccine's safety and understand any potential adverse events (AEs). So, we did this study in Jeddah, Saudi Arabia (SA), from March to May 2022 to compare women who did not get any doses of the COVID-19 vaccine during pregnancy (Group A) to women who did get at least one dose during pregnancy (Group B) regarding (1) the frequency, types, AEs, and management of its AEs of the COVID-19 vaccination; and (2) exploring pregnancy, delivery, and fetus-related complications (e.g., miscarriage, birth defects, and preterm labor)., Methods: A cross-sectional study targeted 438 women who gave birth or were pregnant within the previous 8 weeks. Data was collected through face-to-face interviews with skilled nurses in 13 randomly selected primary healthcare facilities, using a validated, well-structured questionnaire that included the Centers for Disease Control (CDC) COVID-19 vaccination-related AEs. We analyzed the collected data using SPSS version 27., Results: Most participants were aged 25 to less than 35 (58.8%), and 287 (61.3%) were university graduates. There was no statistically significant difference among the studied groups regarding demographics. However, women in Group B had a significantly higher rate of abortions, oligohydramnios (24.4%), abnormal placentas (size and location), 103 (42.7%) abnormal fetal growth, 122 (53.7%) problems breastfeeding, blood pressure problems, and more cases of malaise, headaches, chest pain, breathing problems, and sleep problems than women in Group A. After the second and third doses, the confirmed post-vaccination COVID-19 rates in Group B were lower than those in Group A., Conclusion: The COVID-19 vaccine significantly reduces post-vaccination COVID-19. Although COVID-19 vaccine-related AES are prevalent, analgesics and antipyretics effectively treat most of them., (© The Author(s), 2024.)

Published
2024
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47. A multi-centre longitudinal study analysing multiple sclerosis disease-modifying therapy prescribing patterns during the COVID-19 pandemic.

Author

Lal AP, Foong YC, Sanfilippo PG, Spelman T, Rath L, Levitz D, Fabis-Pedrini M, Foschi M, Habek M, Kalincik T, Roos I, Lechner-Scott J, John N, Soysal A, D'Amico E, Gouider R, Mrabet S, Gross-Paju K, Cárdenas-Robledo S, Moghadasi AN, Sa MJ, Gray O, Oh J, Reddel S, Ramanathan S, Al-Harbi T, Altintas A, Hardy TA, Ozakbas S, Alroughani R, Kermode AG, Surcinelli A, Laureys G, Eichau S, Prat A, Girard M, Duquette P, Hodgkinson S, Ramo-Tello C, Maimone D, McCombe P, Spitaleri D, Sanchez-Menoyo JL, Yetkin MF, Baghbanian SM, Karabudak R, Al-Asmi A, Jakob GB, Khoury SJ, Etemadifar M, van Pesch V, Buzzard K, Taylor B, Butzkueven H, and Van der Walt A

Subjects
Humans, Longitudinal Studies, Male, Female, Adult, Middle Aged, Practice Patterns, Physicians' statistics & numerical data, Immunologic Factors therapeutic use, Cladribine therapeutic use, Alemtuzumab therapeutic use, Multiple Sclerosis drug therapy, Multiple Sclerosis epidemiology, COVID-19 epidemiology, Natalizumab therapeutic use, Fingolimod Hydrochloride therapeutic use, Immunosuppressive Agents therapeutic use
Abstract

Background: The COVID-19 pandemic raised concern amongst clinicians that disease-modifying therapies (DMT), particularly anti-CD20 monoclonal antibodies (mAb) and fingolimod, could worsen COVID-19 in people with multiple sclerosis (pwMS). This study aimed to examine DMT prescribing trends pre- and post-pandemic onset., Methods: A multi-centre longitudinal study with 8,771 participants from MSBase was conducted. Two time periods were defined: pre-pandemic (March 11 2018-March 10 2020) and post-pandemic onset (March 11 2020-11 March 2022). The association between time and prescribing trends was analysed using multivariable mixed-effects logistic regression. DMT initiation refers to first initiation of any DMT, whilst DMT switches indicate changing regimen within 6 months of last use., Results: Post-pandemic onset, there was a significant increase in DMT initiation/switching to natalizumab and cladribine [(Natalizumab-initiation: OR 1.72, 95% CI 1.39-2.13; switching: OR 1.66, 95% CI 1.40-1.98), (Cladribine-initiation: OR 1.43, 95% CI 1.09-1.87; switching: OR 1.67, 95% CI 1.41-1.98)]. Anti-CD20mAb initiation/switching decreased in the year of the pandemic, but recovered in the second year, such that overall odds increased slightly post-pandemic (initiation: OR 1.26, 95% CI 1.06-1.49; Switching: OR 1.15, 95% CI 1.02-1.29. Initiation/switching of fingolimod, interferon-beta, and alemtuzumab significantly decreased [(Fingolimod-initiation: OR 0.55, 95% CI 0.41-0.73; switching: OR 0.49, 95% CI 0.41-0.58), (Interferon-gamma-initiation: OR 0.48, 95% CI 0.41-0.57; switching: OR 0.78, 95% CI 0.62-0.99), (Alemtuzumab-initiation: OR 0.27, 95% CI 0.15-0.48; switching: OR 0.27, 95% CI 0.17-0.44)]., Conclusions: Post-pandemic onset, clinicians preferentially prescribed natalizumab and cladribine over anti-CD20 mAbs and fingolimod, likely to preserve efficacy but reduce perceived immunosuppressive risks. This could have implications for disease progression in pwMS. Our findings highlight the significance of equitable DMT access globally, and the importance of evidence-based decision-making in global health challenges., (© 2024. The Author(s).)

Published
2024
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48. Machine-learning-based prediction of disability progression in multiple sclerosis: An observational, international, multi-center study.

Author

De Brouwer E, Becker T, Werthen-Brabants L, Dewulf P, Iliadis D, Dekeyser C, Laureys G, Van Wijmeersch B, Popescu V, Dhaene T, Deschrijver D, Waegeman W, De Baets B, Stock M, Horakova D, Patti F, Izquierdo G, Eichau S, Girard M, Prat A, Lugaresi A, Grammond P, Kalincik T, Alroughani R, Grand'Maison F, Skibina O, Terzi M, Lechner-Scott J, Gerlach O, Khoury SJ, Cartechini E, Van Pesch V, Sà MJ, Weinstock-Guttman B, Blanco Y, Ampapa R, Spitaleri D, Solaro C, Maimone D, Soysal A, Iuliano G, Gouider R, Castillo-Triviño T, Sánchez-Menoyo JL, Laureys G, van der Walt A, Oh J, Aguera-Morales E, Altintas A, Al-Asmi A, de Gans K, Fragoso Y, Csepany T, Hodgkinson S, Deri N, Al-Harbi T, Taylor B, Gray O, Lalive P, Rozsa C, McGuigan C, Kermode A, Sempere AP, Mihaela S, Simo M, Hardy T, Decoo D, Hughes S, Grigoriadis N, Sas A, Vella N, Moreau Y, and Peeters L

Abstract

Background: Disability progression is a key milestone in the disease evolution of people with multiple sclerosis (PwMS). Prediction models of the probability of disability progression have not yet reached the level of trust needed to be adopted in the clinic. A common benchmark to assess model development in multiple sclerosis is also currently lacking., Methods: Data of adult PwMS with a follow-up of at least three years from 146 MS centers, spread over 40 countries and collected by the MSBase consortium was used. With basic inclusion criteria for quality requirements, it represents a total of 15, 240 PwMS. External validation was performed and repeated five times to assess the significance of the results. Transparent Reporting for Individual Prognosis Or Diagnosis (TRIPOD) guidelines were followed. Confirmed disability progression after two years was predicted, with a confirmation window of six months. Only routinely collected variables were used such as the expanded disability status scale, treatment, relapse information, and MS course. To learn the probability of disability progression, state-of-the-art machine learning models were investigated. The discrimination performance of the models is evaluated with the area under the receiver operator curve (ROC-AUC) and under the precision recall curve (AUC-PR), and their calibration via the Brier score and the expected calibration error. All our preprocessing and model code are available at https://gitlab.com/edebrouwer/ms&#95;benchmark, making this task an ideal benchmark for predicting disability progression in MS., Findings: Machine learning models achieved a ROC-AUC of 0⋅71 ± 0⋅01, an AUC-PR of 0⋅26 ± 0⋅02, a Brier score of 0⋅1 ± 0⋅01 and an expected calibration error of 0⋅07 ± 0⋅04. The history of disability progression was identified as being more predictive for future disability progression than the treatment or relapses history., Conclusions: Good discrimination and calibration performance on an external validation set is achieved, using only routinely collected variables. This suggests machine-learning models can reliably inform clinicians about the future occurrence of progression and are mature for a clinical impact study., Competing Interests: The authors declare no competing non-financial interests but the following competing financial interests: - Dana Horakova received speaker honoraria and consulting fees from Biogen, Merck, Teva, Roche, Sanofi Genzyme, and Novartis, as well as support for research activities from Biogen and Czech Minsitry of Education [project Progres Q27/LF1]. - Francesco Patti received speaker honoraria and advisory board fees from Almirall, Bayer, Biogen, Celgene, Merck, Novartis, Roche, Sanofi-Genzyme and TEVA. He received research funding from Biogen, Merck, FISM (Fondazione Italiana Sclerosi Multipla), Reload Onlus Association and University of Catania. - Guillermo Izquierdo received speaking honoraria from Biogen, Novartis, Sanofi, Merck, Roche, Almirall and Teva. - Sara Eichau received speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche and Teva. - Marc Girard received consulting fees from Teva Canada Innovation, Biogen, Novartis and Genzyme Sanofi; lecture payments from Teva Canada Innovation, Novartis and EMD. He has also received a research grant from Canadian Institutes of Health Research. - Alessandra Lugaresi has served as a Biogen, Bristol Myers Squibb, Merck Serono, Novartis, Roche, Sanofi/ Genzyme and Teva Advisory Board Member. She received congress and travel/accommodation expense compensations or speaker honoraria from Biogen, Merck, Mylan, Novartis, Roche, Sanofi/Genzyme, Teva and Fondazione Italiana Sclerosi Multipla (FISM). Her institutions received research grants from Novartis and Sanofi Genzyme. - Pierre Grammond has served in advisory boards for Novartis, EMD Serono, Roche, Biogen idec, Sanofi Genzyme, Pendopharm and has received grant support from Genzyme and Roche, has received research grants for his institution from Biogen idec, Sanofi Genzyme, EMD Serono. - Tomas Kalincik served on scientific advisory boards for BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Merck and Biogen, steering committee for Brain Atrophy Initiative by Sanofi Genzyme, received conference travel support and/or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Sanofi-Genzyme, Teva, BioCSL and Merck and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene and Merck. - Raed Alroughani received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche and Sanofi-Genzyme. - Francois Grand’Maison received honoraria or research funding from Biogen, Genzyme, Novartis, Teva Neurosciences, Mitsubishi and ONO Pharmaceuticals. - Murat Terzi received travel grants from Novartis, Bayer-Schering, Merck and Teva; has participated in clinical trials by Sanofi Aventis, Roche and Novartis. - Jeannette Lechner-Scott travel compensation from Novartis, Biogen, Roche and Merck. Her institution receives the honoraria for talks and advisory board commitment as well as research grants from Biogen, Merck, Roche, TEVA and Novartis. - Samia J. Khoury received compensation for participation in the Novartis Maestro program. - Vincent van Pesch has received travel grants from Merck, Biogen, Sanofi, Bristol Myers Squibb, Almirall and Roche; his institution receives honoraria for consultancy and lectures and research grants from Roche, Biogen, Sanofi, Merck, Bristol Myers Squibb, Janssen, Almirall and Novartis Pharma. - Radek Ampapa received conference travel support from Novartis, Teva, Biogen, Bayer and Merck and has participated in a clinical trials by Biogen, Novartis, Teva and Actelion. - Daniele Spitaleri received honoraria as a consultant on scientific advisory boards by Bayer-Schering, Novartis and Sanofi-Aventis and compensation for travel from Novartis, Biogen, Sanofi Aventis, Teva and Merck. - Claudio Solaro served on scientific advisory boards for Merck, Genzyme, Almirall, and Biogen; received honoraria and travel grants from Sanofi Aventis, Novartis, Biogen, Merck, Genzyme and Teva. - Davide Maimone served on scientific advisory boards for Bayer, Biogen, Merck, Sanofi-Genzyme, Novartis, Roche, and Almirall; received honoraria and travel grants from Sanofi Genzyme, Novartis, Biogen, Merck, and Roche. - Gerardo Iuliano (retired - no PI successor but has approved ongoing use of data) had travel/accommodations/meeting expenses funded by Bayer Schering, Biogen, Merck, Novartis, Sanofi Aventis, and Teva. - Bart Van Wijmeersch received research and travel grants, honoraria for MS-Expert advisor and Speaker fees from Bayer-Schering, Biogen, Sanofi Genzyme, Merck, Novartis, Roche and Teva. - Tamara Castillo Triviño received speaking/consulting fees and/or travel funding from Bayer, Biogen, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. - Jose Luis Sanchez-Menoyo accepted travel compensation from Novartis, Merck and Biogen, speaking honoraria from Biogen, Novartis, Sanofi, Merck, Almirall, Bayer and Teva and has participated in clinical trials by Biogen, Merck and Roche - Guy Laureys received travel and/or consultancy compensation from Sanofi-Genzyme, Roche, Teva, Merck, Novartis, Celgene, Biogen. - Anneke van der Walt served on advisory boards and receives unrestricted research grants from Novartis, Biogen, Merck and Roche She has received speaker’s honoraria and travel support from Novartis, Roche, and Merck. She receives grant support from the National Health and Medical Research Council of Australia and MS Research Australia. - Jiwon Oh has received research funding from the MS Society of Canada, National MS Society, Brain Canada, Biogen, Roche, EMD Serono (an affiliate of Merck KGaA); and personal compensation for consulting or speaking from Alexion, Biogen, Celgene (BMS), EMD Serono (an affiliate of Merck KGaA), Novartis, Roche, and Sanofi-Genzyme. - Ayse Altintas received speaker honoraria from Merck, Alexion,; received travel and registration grants from Merck, Biogen - Gen Pharma, Roche, Sanofi-Genzyme. - Yara Fragoso received honoraria as a consultant on scientific advisory boards by Novartis, Teva, Roche and Sanofi-Aventis and compensation for travel from Novartis, Biogen, Sanofi Aventis, Teva, Roche and Merck. - Tunde Csepany received speaker honoraria/ conference travel support from Bayer Schering, Biogen, Merck, Novartis, Roche, Sanofi-Aventis and Teva. - Suzanne Hodgkinson received honoraria and consulting fees from Novartis, Bayer Schering and Sanofi, and travel grants from Novartis, Biogen Idec and Bayer Schering. - Norma Deri received funding from Bayer, Merck, Biogen, Genzyme and Novartis. - Bruce Taylor received funding for travel and speaker honoraria from Bayer Schering Pharma, CSL Australia, Biogen and Novartis, and has served on advisory boards for Biogen, Novartis, Roche and CSL Australia. - Fraser Moore participated in clinical trials sponsored by EMD Serono and Novartis. - Orla Gray received honoraria as consultant on scientific advisory boards for Genzyme, Biogen, Merck, Roche and Novartis; has received travel grants from Biogen, Merck, Roche and Novartis; has participated in clinical trials by Biogen and Merck. - Csilla Rozsa received speaker honoraria from Bayer Schering, Novartis and Biogen, congress and travel expense compensations from Biogen, Teva, Merck and Bayer Schering. - Allan Kermode received speaker honoraria and scientific advisory board fees from Bayer, BioCSL, Biogen, Genzyme, Innate Immunotherapeutics, Merck, Novartis, Sanofi, Sanofi-Aventis, and Teva. - Magdolna Simo received speaker honoraria from Novartis, Biogen, Bayer Schering; congress/travel compensation from Teva, Biogen, Merck, Bayer Schering. - Todd Hardy has received speaking fees or received honoraria for serving on advisory boards for Biogen, Merck, Teva, Novartis, Roche, Bristol-Myers Squibb and Sanofi-Genzyme, is Co-Editor of Advances in Clinical Neurosciences and Rehabilitation, and serves on the editorial board of Journal of Neuroimmunology and Frontiers in Neurology. - Nikolaos Grigoriadis received honoraria, consultancy/lecture fees, travel support and research grants from Biogen Idec, Biologix, Novartis, TEVA, Bayer, Merck Serono, Genesis Pharma, Sanofi – Genzyme, ROCHE, Cellgene, ELPEN and research grants from Hellenic Ministry of Development., (Copyright: © 2024 De Brouwer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Published
2024
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49. Examining the environmental risk factors of progressive-onset and relapsing-onset multiple sclerosis: recruitment challenges, potential bias, and statistical strategies.

Author

Li Y, Saul A, Taylor B, Ponsonby AL, Simpson-Yap S, Blizzard L, Broadley S, Lechner-Scott J, Karabudak R, Patti F, Eichau S, Onofrj M, Ozakbas S, Horakova D, Kubala Havrdova E, Grand'Maison F, Alroughani R, Gerlach O, Amato MP, Altintas A, Girard M, Duquette P, Blanco Y, Ramo-Tello C, Laureys G, Kalincik T, Khoury SJ, Shaygannejad V, Etemadifar M, Singhal B, Mrabet S, Foschi M, Habek M, John N, Hughes S, McCombe P, Ampapa R, van der Walt A, Butzkueven H, de Gans K, McGuigan C, Oreja-Guevara C, Sa MJ, Petersen T, Al-Harbi T, Sempere AP, Van Wijmeersch B, Grigoriadis N, Prevost J, Gray O, Castillo-Triviño T, Macdonell R, Lugaresi A, Sajedi SA, and van der Mei I

Subjects
Adult, Female, Humans, Male, Middle Aged, Age of Onset, Australia epidemiology, Case-Control Studies, Recurrence, Risk Factors, Multicenter Studies as Topic, Multiple Sclerosis epidemiology, Multiple Sclerosis etiology, Multiple Sclerosis, Chronic Progressive epidemiology, Multiple Sclerosis, Chronic Progressive etiology
Abstract

It is unknown whether the currently known risk factors of multiple sclerosis reflect the etiology of progressive-onset multiple sclerosis (POMS) as observational studies rarely included analysis by type of onset. We designed a case-control study to examine associations between environmental factors and POMS and compared effect sizes to relapse-onset MS (ROMS), which will offer insights into the etiology of POMS and potentially contribute to prevention and intervention practice. This study utilizes data from the Primary Progressive Multiple Sclerosis (PPMS) Study and the Australian Multi-center Study of Environment and Immune Function (the AusImmune Study). This report outlines the conduct of the PPMS Study, whether the POMS sample is representative, and the planned analysis methods. The study includes 155 POMS, 204 ROMS, and 558 controls. The distributions of the POMS were largely similar to Australian POMS patients in the MSBase Study, with 54.8% female, 85.8% POMS born before 1970, mean age of onset of 41.44 ± 8.38 years old, and 67.1% living between 28.9 and 39.4° S. The POMS were representative of the Australian POMS population. There are some differences between POMS and ROMS/controls (mean age at interview: POMS 55 years vs. controls 40 years; sex: POMS 53% female vs. controls 78% female; location of residence: 14.3% of POMS at a latitude ≤ 28.9°S vs. 32.8% in controls), which will be taken into account in the analysis. We discuss the methodological issues considered in the study design, including prevalence-incidence bias, cohort effects, interview bias and recall bias, and present strategies to account for it. Associations between exposures of interest and POMS/ROMS will be presented in subsequent publications., (© 2023. The Author(s).)

Published
2024
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50. The risk of secondary progressive multiple sclerosis is geographically determined but modifiable.

Author

Sharmin S, Roos I, Simpson-Yap S, Malpas C, Sánchez MM, Ozakbas S, Horakova D, Havrdova EK, Patti F, Alroughani R, Izquierdo G, Eichau S, Boz C, Zakaria M, Onofrj M, Lugaresi A, Weinstock-Guttman B, Prat A, Girard M, Duquette P, Terzi M, Amato MP, Karabudak R, Grand'Maison F, Khoury SJ, Grammond P, Lechner-Scott J, Buzzard K, Skibina O, van der Walt A, Butzkueven H, Turkoglu R, Altintas A, Maimone D, Kermode A, Shalaby N, Pesch VV, Butler E, Sidhom Y, Gouider R, Mrabet S, Gerlach O, Soysal A, Barnett M, Kuhle J, Hughes S, Sa MJ, Hodgkinson S, Oreja-Guevara C, Ampapa R, Petersen T, Ramo-Tello C, Spitaleri D, McCombe P, Taylor B, Prevost J, Foschi M, Slee M, McGuigan C, Laureys G, Hijfte LV, de Gans K, Solaro C, Oh J, Macdonell R, Aguera-Morales E, Singhal B, Gray O, Garber J, Wijmeersch BV, Simu M, Castillo-Triviño T, Sanchez-Menoyo JL, Khurana D, Al-Asmi A, Al-Harbi T, Deri N, Fragoso Y, Lalive PH, Sinnige LGF, Shaw C, Shuey N, Csepany T, Sempere AP, Moore F, Decoo D, Willekens B, Gobbi C, Massey J, Hardy T, Parratt J, and Kalincik T

Subjects
Humans, Ultraviolet Rays, Disease Progression, Neoplasm Recurrence, Local, Multiple Sclerosis, Chronic Progressive epidemiology, Multiple Sclerosis epidemiology, Multiple Sclerosis diagnosis, Multiple Sclerosis, Relapsing-Remitting epidemiology
Abstract

Geographical variations in the incidence and prevalence of multiple sclerosis have been reported globally. Latitude as a surrogate for exposure to ultraviolet radiation but also other lifestyle and environmental factors are regarded as drivers of this variation. No previous studies evaluated geographical variation in the risk of secondary progressive multiple sclerosis, an advanced form of multiple sclerosis that is characterized by steady accrual of irreversible disability. We evaluated differences in the risk of secondary progressive multiple sclerosis in relation to latitude and country of residence, modified by high-to-moderate efficacy immunotherapy in a geographically diverse cohort of patients with relapsing-remitting multiple sclerosis. The study included relapsing-remitting multiple sclerosis patients from the global MSBase registry with at least one recorded assessment of disability. Secondary progressive multiple sclerosis was identified as per clinician diagnosis. Sensitivity analyses used the operationalized definition of secondary progressive multiple sclerosis and the Swedish decision tree algorithm. A proportional hazards model was used to estimate the cumulative risk of secondary progressive multiple sclerosis by country of residence (latitude), adjusted for sex, age at disease onset, time from onset to relapsing-remitting phase, disability (Multiple Sclerosis Severity Score) and relapse activity at study inclusion, national multiple sclerosis prevalence, government health expenditure, and proportion of time treated with high-to-moderate efficacy disease-modifying therapy. Geographical variation in time from relapsing-remitting phase to secondary progressive phase of multiple sclerosis was modelled through a proportional hazards model with spatially correlated frailties. We included 51 126 patients (72% female) from 27 countries. The median survival time from relapsing-remitting phase to secondary progressive multiple sclerosis among all patients was 39 (95% confidence interval: 37 to 43) years. Higher latitude [median hazard ratio = 1.21, 95% credible interval (1.16, 1.26)], higher national multiple sclerosis prevalence [1.07 (1.03, 1.11)], male sex [1.30 (1.22, 1.39)], older age at onset [1.35 (1.30, 1.39)], higher disability [2.40 (2.34, 2.47)] and frequent relapses [1.18 (1.15, 1.21)] at inclusion were associated with increased hazard of secondary progressive multiple sclerosis. Higher proportion of time on high-to-moderate efficacy therapy substantially reduced the hazard of secondary progressive multiple sclerosis [0.76 (0.73, 0.79)] and reduced the effect of latitude [interaction: 0.95 (0.92, 0.99)]. At the country-level, patients in Oman, Tunisia, Iran and Canada had higher risks of secondary progressive multiple sclerosis relative to the other studied regions. Higher latitude of residence is associated with a higher probability of developing secondary progressive multiple sclerosis. High-to-moderate efficacy immunotherapy can mitigate some of this geographically co-determined risk., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Published
2023
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