Medicine (RMH) - Research Publications

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    Effect of Disease-Modifying Therapy on Disability in Relapsing-Remitting Multiple Sclerosis Over 15 Years
    Kalincik, T ; Diouf, I ; Sharmin, S ; Malpas, C ; Spelman, T ; Horakova, D ; Havrdova, EK ; Trojano, M ; Izquierdo, G ; Lugaresi, A ; Prat, A ; Girard, M ; Duquette, P ; Grammond, P ; Jokubaitis, V ; Van der Walt, A ; Grand'Maison, F ; Sola, P ; Ferraro, D ; Shaygannejad, V ; Alroughani, R ; Hupperts, R ; Terzi, M ; Boz, C ; Lechner-Scott, J ; Pucci, E ; Van Pesch, V ; Granella, F ; Bergamaschi, R ; Spitaleri, D ; Slee, M ; Vucic, S ; Ampapa, R ; McCombe, P ; Ramo-Tello, C ; Prevost, J ; Olascoaga, J ; Cristiano, E ; Barnett, M ; Saladino, ML ; Sanchez-Menoyo, JL ; Hodgkinson, S ; Rozsa, C ; Hughes, S ; Moore, F ; Shaw, C ; Butler, E ; Skibina, O ; Gray, O ; Kermode, A ; Csepany, T ; Singhal, B ; Shuey, N ; Piroska, I ; Taylor, B ; Simo, M ; Sirbu, C-A ; Sas, A ; Butzkueven, H (LIPPINCOTT WILLIAMS & WILKINS, 2021-02-02)
    OBJECTIVE: To test the hypothesis that immunotherapy prevents long-term disability in relapsing-remitting multiple sclerosis (MS), we modeled disability outcomes in 14,717 patients. METHODS: We studied patients from MSBase followed for ≥1 year, with ≥3 visits, ≥1 visit per year, and exposed to MS therapy, and a subset of patients with ≥15-year follow-up. Marginal structural models were used to compare the cumulative hazards of 12-month confirmed increase and decrease in disability, Expanded Disability Status Scale (EDSS) step 6, and the incidence of relapses between treated and untreated periods. Marginal structural models were continuously readjusted for patient age, sex, pregnancy, date, disease course, time from first symptom, prior relapse history, disability, and MRI activity. RESULTS: A total of 14,717 patients were studied. During the treated periods, patients were less likely to experience relapses (hazard ratio 0.60, 95% confidence interval [CI] 0.43-0.82, p = 0.0016), worsening of disability (0.56, 0.38-0.82, p = 0.0026), and progress to EDSS step 6 (0.33, 0.19-0.59, p = 0.00019). Among 1,085 patients with ≥15-year follow-up, the treated patients were less likely to experience relapses (0.59, 0.50-0.70, p = 10-9) and worsening of disability (0.81, 0.67-0.99, p = 0.043). CONCLUSION: Continued treatment with MS immunotherapies reduces disability accrual by 19%-44% (95% CI 1%-62%), the risk of need of a walking aid by 67% (95% CI 41%-81%), and the frequency of relapses by 40-41% (95% CI 18%-57%) over 15 years. This study provides evidence that disease-modifying therapies are effective in improving disability outcomes in relapsing-remitting MS over the long term. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that, for patients with relapsing-remitting MS, long-term exposure to immunotherapy prevents neurologic disability.
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    Psychometric deficits in autoimmune encephalitis: A retrospective study from the Australian Autoimmune Encephalitis Consortium
    Griffith, S ; Wesselingh, R ; Broadley, J ; O'Shea, M ; Kyndt, C ; Meade, C ; Long, B ; Seneviratne, U ; Reidy, N ; Bourke, R ; Buzzard, K ; D'Souza, W ; Macdonell, R ; Brodtmann, A ; Butzkueven, H ; O'Brien, TJ ; Alpitsis, R ; Malpas, CB ; Monif, M (WILEY, 2022-08)
    BACKGROUND AND PURPOSE: Despite the rapid increase in research examining outcomes in autoimmune encephalitis (AE) patients, there are few cohort studies examining cognitive outcomes in this population. The current study aimed to characterise psychometric outcomes in this population, and explore variables that may predict psychometric outcomes. METHODS: This retrospective observational study collected psychometric data from 59 patients across six secondary and tertiary referral centres in metropolitan hospitals in Victoria, Australia between January 2008 and July 2019. Frequency and pattern analysis were employed to define and characterize psychometric outcomes. Univariable logistic regression was performed to examine predictors of intact and pathological psychometric outcomes. RESULTS: Deficits in psychometric markers of executive dysfunction were the most common finding in this cohort, followed by deficits on tasks sensitive to memory. A total of 54.2% of patients were classified as having psychometric impairments across at least two cognitive domains. Twenty-nine patterns were observed, suggesting outcomes in AE are complex. None of the demographic data, clinical features or auxiliary examination variables were predictors of psychometric outcome. CONCLUSIONS: Cognitive outcomes in AE are complex. Further detailed and standardized cognitive testing, in combination with magnetic resonance imaging volumetrics and serum/cerebrospinal fluid biomarkers, is required to provide rigorous assessments of disease outcomes.
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    Timely intervention, monitoring and education MATTERS in MS (TIME MATTERS in MS): Development of a globally applicable quality improvement tool.
    Hobart, J ; Butzkueven, H ; Haartsen, J ; Ziemssen, T ; Lane, T ; Giovannoni, G (SAGE Publishing, 2022)
    BACKGROUND: Previously, consensus MS care standards were defined by MS specialist neurologists from 19 countries. We developed, piloted and refined an Excel-based quality improvement tool to enable MS services to benchmark against these standards. Here, we examine the refined tool. OBJECTIVE: To determine the applicability of the quality improvement tool in different healthcare settings. METHODS: MS centres across the globe were invited to pilot the quality improvement tool by coding the medical records of 36 adults with MS. We invited feedback on user friendliness, quality improvement tool usefulness and relevance of data collected. RESULTS: Seventeen centres from 14 countries participated; 14 completed the post-service evaluation survey. Over 50% of responders rated the tool 'very easy' or 'easy' to use and 'very relevant' to their service. Almost 85% of responders (11/13) planned to introduce changes to their service, including improvements in documentation, communication, interactions with colleagues and referrals; 85% would use a future shorter version of the tool. CONCLUSIONS: The quality improvement tool can enable MS centres globally to benchmark their services. Widespread uptake of a shorter tool may help MS centres to work towards achieving consensus standards for brain health-focused care. Incorporation into routine clinical practice would drive adoption.
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    Association of Latitude and Exposure to Ultraviolet B Radiation With Severity of Multiple Sclerosis An International Registry Study
    Vitkova, M ; Diouf, I ; Malpas, C ; Horakova, D ; Havrdova, EK ; Patti, F ; Ozakbas, S ; Izquierdo, G ; Eichau, S ; Shaygannejad, V ; Onofrj, M ; Lugaresi, A ; Alroughani, R ; Prat, A ; Larochelle, C ; Girard, M ; Duquette, P ; Terzi, M ; Boz, C ; Grand'Maison, F ; Sola, P ; Ferraro, D ; Grammond, P ; Butzkueven, H ; Buzzard, K ; Skibina, O ; Yamout, B ; Karabudak, R ; Gerlach, O ; Lechner-Scott, J ; Maimone, D ; Bergamaschi, R ; Van Pesch, V ; Iuliano, G ; Cartechini, E ; Sa, MJ ; Ampapa, R ; Barnett, M ; Hughes, SE ; Ramo-Tello, CM ; Hodgkinson, S ; Spitaleri, DLA ; Petersen, T ; Butler, EG ; Slee, M ; McGuigan, C ; McCombe, PA ; Granella, F ; Cristiano, E ; Prevost, J ; Taylor, B ; Sanchez-Menoyo, JL ; Laureys, G ; Van Hijfte, L ; Vucic, S ; Macdonell, RA ; Gray, O ; Olascoaga, J ; Deri, N ; Fragoso, YD ; Shaw, C ; Kalincik, T (LIPPINCOTT WILLIAMS & WILKINS, 2022-06-14)
    BACKGROUND AND OBJECTIVES: The severity of multiple sclerosis (MS) varies widely among individuals. Understanding the determinants of this heterogeneity will help clinicians optimize the management of MS. The aim of this study was to investigate the association between latitude of residence, UV B radiation (UVB) exposure, and the severity of MS. METHODS: This observational study used the MSBase registry data. The included patients met the 2005 or 2010 McDonald diagnostic criteria for MS and had a minimum dataset recorded in the registry (date of birth, sex, clinic location, date of MS symptom onset, disease phenotype at baseline and censoring, and ≥1 Expanded Disability Status Scale score recorded). The latitude of each study center and cumulative annualized UVB dose at study center (calculated from National Aeronautics and Space Administration's Total Ozone Mapping Spectrometer) at ages 6 and 18 years and the year of disability assessment were calculated. Disease severity was quantified with Multiple Sclerosis Severity Score (MSSS). Quadratic regression was used to model the associations between latitude, UVB, and MSSS. RESULTS: The 46,128 patients who contributed 453,208 visits and a cumulative follow-up of 351,196 patient-years (70% women, mean age 39.2 ± 12 years, resident between latitudes 19°35' and 56°16') were included in this study. Latitude showed a nonlinear association with MS severity. In latitudes <40°, more severe disease was associated with higher latitudes (β = 0.08, 95% CI 0.04-0.12). For example, this translates into a mean difference of 1.3 points of MSSS between patients living in Madrid and Copenhagen. No such association was observed in latitudes <40° (β = -0.02, 95% CI -0.06 to 0.03). The overall disability accrual was faster in those with a lower level of estimated UVB exposure before the age of 6 years (β = - 0.5, 95% CI -0.6 to 0.4) and 18 years (β = - 0.6, 95% CI -0.7 to 0.4), as well as with lower lifetime UVB exposure at the time of disability assessment (β = -1.0, 95% CI -1.1 to 0.9). DISCUSSION: In temperate zones, MS severity is associated with latitude. This association is mainly, but not exclusively, driven by UVB exposure contributing to both MS susceptibility and severity.
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    Disease Reactivation After Cessation of Disease-Modifying Therapy in Patients With Relapsing-Remitting Multiple Sclerosis
    Roos, I ; Malpas, C ; Leray, E ; Casey, R ; Horakova, D ; Havrdova, EK ; Debouverie, M ; Patti, F ; De Seze, J ; Izquierdo, G ; Eichau, S ; Edan, G ; Prat, A ; Girard, M ; Ozakbas, S ; Grammond, P ; Zephir, H ; Ciron, J ; Maillart, E ; Moreau, T ; Amato, MP ; Labauge, P ; Alroughani, R ; Buzzard, K ; Skibina, O ; Terzi, M ; Laplaud, DA ; Berger, E ; Grand'Maison, F ; Lebrun-Frenay, C ; Cartechini, E ; Boz, C ; Lechner-Scott, J ; Clavelou, P ; Stankoff, B ; Prevost, J ; Kappos, L ; Pelletier, J ; Shaygannejad, V ; Yamout, B ; Khoury, SJ ; Gerlach, O ; Spitaleri, DLA ; Van Pesch, V ; Gout, O ; Turkoglu, R ; Heinzlef, O ; Thouvenot, E ; McCombe, PA ; Soysal, A ; Bourre, B ; Slee, M ; Castillo-Trivino, T ; Bakchine, S ; Ampapa, R ; Butler, EG ; Wahab, A ; Macdonell, RA ; Aguera-Morales, E ; Cabre, P ; Ben, NH ; Van der Walt, A ; Laureys, G ; Van Hijfte, L ; Ramo-Tello, CM ; Maubeuge, N ; Hodgkinson, S ; Sanchez-Menoyo, JL ; Barnett, MH ; Labeyrie, C ; Vucic, S ; Sidhom, Y ; Gouider, R ; Csepany, T ; Sotoca, J ; de Gans, K ; Al-Asmi, A ; Fragoso, YD ; Vukusic, S ; Butzkueven, H ; Kalincik, T (LIPPINCOTT WILLIAMS & WILKINS, 2022-10-25)
    BACKGROUND AND OBJECTIVES: To evaluate the rate of return of disease activity after cessation of multiple sclerosis (MS) disease-modifying therapy. METHODS: This was a retrospective cohort study from 2 large observational MS registries: MSBase and OFSEP. Patients with relapsing-remitting MS who had ceased a disease-modifying therapy and were followed up for the subsequent 12 months were included in the analysis. The primary study outcome was annualized relapse rate in the 12 months after disease-modifying therapy discontinuation stratified by patients who did, and did not, commence a subsequent therapy. The secondary endpoint was the predictors of first relapse and disability accumulation after treatment discontinuation. RESULTS: A total of 14,213 patients, with 18,029 eligible treatment discontinuation epochs, were identified for 7 therapies. Annualized rates of relapse (ARRs) started to increase 2 months after natalizumab cessation (month 2-4 ARR 0.47, 95% CI 0.43-0.51). Commencement of a subsequent therapy within 2-4 months reduced the magnitude of disease reactivation (mean ARR difference: 0.15, 0.08-0.22). After discontinuation of fingolimod, rates of relapse increased overall (month 1-2 ARR: 0.80, 0.70-0.89) and stabilized faster in patients who started a new therapy within 1-2 months (mean ARR difference: 0.14, -0.01 to 0.29). The magnitude of disease reactivation for other therapies was low but reduced further by commencement of another treatment 1-10 months after treatment discontinuation. Predictors of relapse were a higher relapse rate in the year before cessation, female sex, younger age, and higher EDSS score. Commencement of a subsequent therapy reduced both the risk of relapse (HR 0.76, 95% CI 0.72-0.81) and disability accumulation (0.73, 0.65-0.80). DISCUSSION: The rate of disease reactivation after treatment cessation differs among MS treatments, with the peaks of relapse activity ranging from 1 to 10 months in untreated cohorts that discontinued different therapies. These results suggest that untreated intervals should be minimized after stopping antitrafficking therapies (natalizumab and fingolimod). CLASSIFICATION OF EVIDENCE: This study provides Class III that disease reactivation occurs within months of discontinuation of MS disease-modifying therapies. The risk of disease activity is reduced by commencement of a subsequent therapy.
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    Multiple Sclerosis Severity Score (MSSS) improves the accuracy of individualized prediction in MS
    Kalincik, T ; Kister, I ; Bacon, TE ; Malpas, CB ; Sharmin, S ; Horakova, D ; Kubala-Havrdova, E ; Patti, F ; Izquierdo, G ; Eichau, S ; Ozakbas, S ; Onofrj, M ; Lugaresi, A ; Prat, A ; Girard, M ; Duquette, P ; Grammond, P ; Sola, P ; Ferraro, D ; Alroughani, R ; Terzi, M ; Boz, C ; Grand'Maison, F ; Bergamaschi, R ; Gerlach, O ; Sa, MJ ; Kappos, L ; Cartechini, E ; Lechner-Scott, J ; van Pesch, V ; Shaygannejad, V ; Granella, F ; Spitaleri, D ; Iuliano, G ; Maimone, D ; Prevost, J ; Soysal, A ; Turkoglu, R ; Ampapa, R ; Butzkueven, H ; Cutter, G (SAGE PUBLICATIONS LTD, 2022-10)
    BACKGROUND: The MSBase prediction model of treatment response leverages multiple demographic and clinical characteristics to estimate hazards of relapses, confirmed disability accumulation (CDA), and confirmed disability improvement (CDI). The model did not include Multiple Sclerosis Severity Score (MSSS), a disease duration-adjusted ranked score of disability. OBJECTIVE: To incorporate MSSS into the MSBase prediction model and compare model accuracy with and without MSSS. METHODS: The associations between MSSS and relapse, CDA, and CDI were evaluated with marginal proportional hazards models adjusted for three principal components representative of patients' demographic and clinical characteristics. The model fit with and without MSSS was assessed with penalized r2 and Harrell C. RESULTS: A total of 5866 MS patients were started on disease-modifying therapy during prospective follow-up (age 38.4 ± 10.6 years; 72% female; disease duration 8.5 ± 7.7 years). Including MSSS into the model improved the accuracy of individual prediction of relapses by 31%, of CDA by 23%, and of CDI by 24% (Harrell C) and increased the amount of variance explained for relapses by 49%, for CDI by 11%, and for CDA by 10% as compared with the original model. CONCLUSION: Addition of a single, readily available metric, MSSS, to the comprehensive MSBase prediction model considerably improved the individual accuracy of prognostics in MS.
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    Severity of COVID19 infection among patients with multiple sclerosis treated with interferon-β
    Simpson-Yap, S ; Pirmani, A ; De Brouwer, E ; Peeters, LM ; Geys, L ; Parciak, T ; Helme, A ; Hillert, J ; Moreau, Y ; Edan, G ; Spelman, T ; Sharmin, S ; McBurney, R ; Schmidt, H ; Bergmann, A ; Braune, S ; Stahmann, A ; Middleton, R ; Salter, A ; Bebo, B ; van der Walt, A ; Butzkueven, H ; Ozakbas, S ; Karabudak, R ; Boz, C ; Alroughani, R ; Rojas, J ; van der Mei, I ; do Olival, GS ; Magyari, M ; Alonso, R ; Nicholas, R ; Chertcoff, A ; Zabalza, A ; Arrambide, G ; Nag, N ; Descamps, A ; Costers, L ; Dobson, R ; Miller, A ; Rodrigues, P ; Prckovska, V ; Comi, G ; Kalincik, T (ELSEVIER SCI LTD, 2022-10)
    BACKGROUND: Interferon-β, a disease-modifying therapy (DMT) for MS, may be associated with less severe COVID-19 in people with MS. RESULTS: Among 5,568 patients (83.4% confirmed COVID-19), interferon-treated patients had lower risk of severe COVID-19 compared to untreated, but not to glatiramer-acetate, dimethyl-fumarate, or pooled other DMTs. CONCLUSIONS: In comparison to other DMTs, we did not find evidence of protective effects of interferon-β on the severity of COVID-19, though compared to the untreated, the course of COVID19 was milder among those on interferon-β. This study does not support the use of interferon-β as a treatment to reduce COVID-19 severity in MS.
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    Confirmed disability progression as a marker of permanent disability in multiple sclerosis
    Sharmin, S ; Malpas, C ; Lechner-Scott, J ; Slee, M ; McCombe, P ; Vucic, S ; Butler, E ; Hodgkinson, S ; Barnett, M ; Skibina, O ; van der Walt, A ; Buzzard, K ; Shaw, C ; Kermode, A ; Taylor, B ; Shuey, N ; Macdonell, R ; Butzkueven, H ; Kalincik, T (SAGE PUBLICATIONS LTD, 2022-12)
    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.
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    Gait and balance deterioration over a 12-month period in multiple sclerosis patients with EDSS scores ≤ 3.0
    Galea, MP ; Lizama, LEC ; Butzkueven, H ; Kilpatrick, TJ (IOS PRESS, 2017)
    BACKGROUND AND PURPOSE: It is not currently known whether gait and balance measures are responsive to deterioration of motor function in multiple sclerosis (MS) patients with low EDSS scores (≤3.0). The aim of this study was to quantify MS-related gait and balance deterioration over a 12-month period. METHODS: Thirty-eight participants with MS (33 female, mean age: 41.1 ± 8.3 years), mean time since diagnosis 2.2 ± 4.1 years, EDSS score ≤3.0 and without clinical evidence of gait deterioration, were recruited. Participants performed walking trials and Functional and Lateral Reach Tests. Kinematics of the ankle and knee, and electromyography of the tibialis anterior and medial gastrocnemius muscles were also measured. RESULTS: Three participants reported relapses with worsening EDSS scores and 4 non-relapsing participants had worse EDSS scores at 12 months. There were significant decreases in mean gait speed, stride length and balance scores, and a significant increase in double support. Marked changes in ankle kinematics, with decreased medial gastrocnemius activity were observed. CONCLUSION: Gait and balance performance of non-disabled RRMS participants may progressively decline, even in the absence of both acute clinical relapse and change in clinical status measured by the EDSS.
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    The CLARION study design and status update: a long-term, registry-based study evaluating adverse events of special interest in patients with relapsing multiple sclerosis newly started on cladribine tablets.
    Butzkueven, H ; Moore, N ; Aydemir, A ; Sõnajalg, J ; Bezemer, I ; Korhonen, P ; Sabidó, M ; CLARION Study Group, (Informa UK Limited, 2022-07)
    OBJECTIVE: To describe the design of the CLARION post-approval safety study (EU PAS Register number, EUPAS24484) and provide a status update, including characteristics of patients included up to 1 May 2021. METHODS: CLARION aims to further evaluate adverse events of special interest in patients who are newly initiating treatment with cladribine tablets for relapsing multiple sclerosis (MS). The study population consists of two cohorts: patients newly initiating cladribine tablets (cladribine cohort) and patients newly initiating oral fingolimod tablets (comparator fingolimod cohort), with an aim to include 8000 patients (4000 patients per cohort). The study relies on secondary use of data from pre-existing MS registries/data sources (except in Germany, where primary data collection is performed). The study is projected to last 15 years, with an anticipated 5-year inclusion period. Study outcomes are: malignancies; severe infections; tuberculosis; progressive multifocal leukoencephalopathy; other opportunistic infections; herpes zoster; severe lymphopenia (Grade ≥ 3); and treatment discontinuation. RESULTS: As of 1 May 2021, 2393 patients were included in CLARION from seven participating MS registries/data sources (cladribine cohort, n = 1266; fingolimod cohort, n = 1127). The majority of patients are female (cladribine cohort, 72.5%; fingolimod cohort, 68.0%), with mean age at onset of MS of 31.5 years for the cladribine cohort and 30.9 years for the fingolimod cohort. The majority of patients in both cohorts had relapsing MS (cladribine cohort, 92.1%; fingolimod cohort, 93.5%). CONCLUSION: By providing further information on adverse events of special interest during long-term follow-up, CLARION will assist neurologists and patients regarding treatment decision-making for management of relapsing MS.