Medicine (RMH) - Research Publications

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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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    Prognostic Indicators in Pediatric Clinically Isolated Syndrome
    Iaffaldano, P ; Simone, M ; Lucisano, G ; Ghezzi, A ; Coniglio, G ; Morra, VB ; Salemi, G ; Patti, F ; Lugaresi, A ; Izquierdo, G ; Bergamaschi, R ; Cabrera-Gomez, JA ; Pozzilli, C ; Millefiorini, E ; Alroughani, R ; Boz, C ; Pucci, E ; Zimatore, GB ; Sola, P ; Lus, G ; Maimone, D ; Avolio, C ; Cocco, E ; Sajedi, SA ; Costantino, G ; Duquette, P ; Shaygannejad, V ; Petersen, T ; Fernandez Bolanos, R ; Paolicelli, D ; Tortorella, C ; Spelman, T ; Margari, L ; Amato, MP ; Comi, G ; Butzkueven, H ; Trojano, M (WILEY, 2017-05)
    OBJECTIVE: To assess prognostic factors for a second clinical attack and a first disability-worsening event in pediatric clinically isolated syndrome (pCIS) suggestive of multiple sclerosis (MS) patients. METHODS: A cohort of 770 pCIS patients was followed up for at least 10 years. Cox proportional hazard models and Recursive Partitioning and Amalgamation (RECPAM) tree-regression were used to analyze data. RESULTS: In pCIS, female sex and a multifocal onset were risk factors for a second clinical attack (hazard ratio [HR], 95% confidence interval [CI] = 1.28, 1.06-1.55; 1.42, 1.10-1.84, respectively), whereas disease-modifying drug (DMD) exposure reduced this risk (HR, 95% CI = 0.75, 0.60-0.95). After pediatric onset MS (POMS) diagnosis, age at onset younger than 15 years and DMD exposure decreased the risk of a first Expanded Disability Status Scale (EDSS)-worsening event (HR, 95% CI = 0.59, 0.42-0.83; 0.75, 0.71-0.80, respectively), whereas the occurrence of relapse increased this risk (HR, 95% CI = 5.08, 3.46-7.46). An exploratory RECPAM analysis highlighted a significantly higher incidence of a first EDSS-worsening event in patients with multifocal or isolated spinal cord or optic neuritis involvement at onset in comparison to those with an isolated supratentorial or brainstem syndrome. A Cox regression model including RECPAM classes confirmed DMD exposure as the most protective factor against EDSS-worsening events and relapses as the most important risk factor for attaining EDSS worsening. INTERPRETATION: This work represents a step forward in identifying predictors of unfavorable course in pCIS and POMS and supports a protective effect of early DMD treatment in preventing MS development and disability accumulation in this population. Ann Neurol 2017;81:729-739.
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    Monoclonal antibodies in the treatment of multiple sclerosis: emergence of B-cell-targeted therapies
    Ai-Lan, N ; Gresle, M ; Marshall, T ; Butzkueven, H ; Field, J (WILEY, 2017-07)
    Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS, and one of the most common causes of disability in young adults. Over the last decade, new disease-modifying therapies have emerged, including monoclonal antibodies (mAbs) that provide highly targeted therapies with greater efficacy than platform therapies. In particular, monoclonal antibodies directed against CD20-positive B cells have shown remarkable results in recent clinical trials and renewed interest in the mechanism of B cell-depleting therapies to ameliorate relapse activity and progression in MS. Here, we review the mechanisms of action and clinical evidence of approved and emerging mAbs, with a focus on B cell-targeted therapies.
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    Predictors of Long-Term Disability Accrual in Relapse-Onset Multiple Sclerosis
    Jokubaitis, VG ; Spelman, T ; Kalincik, T ; Lorscheider, J ; Havrdova, E ; Horakova, D ; Duquette, P ; Girard, M ; Prat, A ; Izquierdo, G ; Grammond, P ; Van Pesch, V ; Pucci, E ; Grand'Maison, F ; Hupperts, R ; Granella, F ; Sola, P ; Bergamaschi, R ; Iuliano, G ; Spitaleri, D ; Boz, C ; Hodgkinson, S ; Olascoaga, J ; Verheul, F ; McCombe, P ; Petersen, T ; Rozsa, C ; Lechner-Scott, J ; Laura Saladino, M ; Farina, D ; Iaffaldano, P ; Paolicelli, D ; Butzkueven, H ; Lugaresi, A ; Trojano, M (WILEY, 2016-07)
    OBJECTIVE: To identify predictors of 10-year Expanded Disability Status Scale (EDSS) change after treatment initiation in patients with relapse-onset multiple sclerosis. METHODS: Using data obtained from MSBase, we defined baseline as the date of first injectable therapy initiation. Patients need only have remained on injectable therapy for 1 day and were monitored on any approved disease-modifying therapy, or no therapy thereafter. Median EDSS score changes over a 10-year period were determined. Predictors of EDSS change were then assessed using median quantile regression analysis. Sensitivity analyses were further performed. RESULTS: We identified 2,466 patients followed up for at least 10 years reporting post-baseline disability scores. Patients were treated an average 83% of their follow-up time. EDSS scores increased by a median 1 point (interquartile range = 0-2) at 10 years post-baseline. Annualized relapse rate was highly predictive of increases in median EDSS over 10 years (coeff = 1.14, p = 1.9 × 10(-22) ). On-therapy relapses carried greater burden than off-therapy relapses. Cumulative treatment exposure was independently associated with lower EDSS at 10 years (coeff = -0.86, p = 1.3 × 10(-9) ). Furthermore, pregnancies were also independently associated with lower EDSS scores over the 10-year observation period (coeff = -0.36, p = 0.009). INTERPRETATION: We provide evidence of long-term treatment benefit in a large registry cohort, and provide evidence of long-term protective effects of pregnancy against disability accrual. We demonstrate that high annualized relapse rate, particularly on-treatment relapse, is an indicator of poor prognosis. Ann Neurol 2016;80:89-100.
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    Risk of early relapse following the switch from injectables to oral agents for multiple sclerosis
    Spelman, T ; Mekhael, L ; Burke, T ; Butzkueven, H ; Hodgkinson, S ; Havrdova, E ; Horakova, D ; Duquette, P ; Izquierdo, G ; Grand'Maison, F ; Grammond, P ; Barnett, M ; Lechner-Scott, J ; Alroughani, R ; Trojano, M ; Lugaresi, A ; Granella, F ; Pucci, E ; Vucic, S (WILEY, 2016-04)
    BACKGROUND AND PURPOSE: Early relapse outcomes in long-term stable patients switching from interferon β/glatiramer acetate (IFNβ/GA) to oral therapy are unknown. OBJECTIVE: The objective of this study was to compare early relapse and progression in multiple sclerosis (MS) patients switching to oral therapy following a period of stable disease on IFNβ/GA, relative to a propensity-matched comparator of patients remaining on IFNβ/GA. METHODS: The MSBase cohort study is a global, longitudinal registry for MS. Time to first 6-month relapse in previously stable MS patients switching from platform injectables ('switchers') to oral agents were compared with propensity-matched patients remaining on IFNβ/GA ('stayers') using a Cox marginal model. RESULTS: Three-hundred and ninety-six switchers were successfully matched to 396 stayers on a 1:1 basis. There was no difference in the proportion of patients recording at least one relapse in the first 1-6 months by treatment arm (7.3% switchers, 6.6% stayers; P = 0.675). The mean annualized relapse rate (P = 0.493) and the rate of first 6-month relapse by treatment arm (hazard ratio 1.22, 95% confidence interval 0.70, 2.11) were also comparable. There was no difference in the rate of disability progression by treatment arm (hazard ratio 1.43, 95% confidence interval 0.63, 3.26). CONCLUSION: This is the first study to compare early relapse switch probability in the period immediately following switch to oral treatment in a population previously stable on injectable therapy. There was no evidence of disease reactivation within the first 6 months of switching to oral therapy.
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    Anti-inflammatory disease-modifying treatment and disability progression in primary progressive multiple sclerosis: a cohort study
    Lorscheider, J ; Kuhle, J ; Izquierdo, G ; Lugaresi, A ; Havrdova, E ; Horakova, D ; Hupperts, R ; Duquette, P ; Girard, M ; Prat, A ; Grand'Maison, F ; Grammond, P ; Sola, P ; Ferraro, D ; Trojano, M ; Ramo-Tello, C ; Lechner-Scott, J ; Pucci, E ; Solaro, C ; Slee, M ; Van Pesch, V ; Sanchez Menoyo, JL ; van der Walt, A ; Butzkueven, H ; Kappos, L ; Kalincik, T (WILEY, 2019-02)
    BACKGROUND AND PURPOSE: Treatment options in primary progressive multiple sclerosis (PPMS) are scarce and, with the exception of ocrelizumab, anti-inflammatory agents have failed to show efficacy in ameliorating disability progression. The aim of this study was to investigate a potential effect of anti-inflammatory disease-modifying treatment on disability outcomes in PPMS. METHODS: Using MSBase, a large, international, observational database, we identified patients with PPMS who were either never treated or treated with a disease-modifying agent. Propensity score matching was used to select subpopulations with similar baseline characteristics. Expanded Disability Status Scale (EDSS) outcomes were compared with an intention-to-treat and an as-treated approach in paired, pairwise-censored analyses. RESULTS: Of the 1284 included patients, 533 were matched (treated, n = 195; untreated n = 338). Median on-study pairwise-censored follow-up was 3.4 years (quartiles 1.2-5.5). No difference in the hazard of experiencing 3-month confirmed EDSS progression events was observed between the groups [hazard ratio (HR), 1.0; 95% confidence interval (CI), 0.6-1.7, P = 0.87]. We did not find significant differences in the hazards of confirmed EDSS improvement (HR, 1.0; 95% CI, 0.6-1.6, P = 0.91) or reaching a confirmed EDSS step ≥7 (HR, 1.1; 95% CI, 0.7-1.6, P = 0.69). CONCLUSION: Our pooled analysis of disease-modifying agents suggests that these therapies have no substantial effect on short- to medium-term disability outcomes in PPMS.
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    Evaluation of pregnancy outcomes in patients with multiple sclerosis after fingolimod exposure.
    Geissbühler, Y ; Vile, J ; Koren, G ; Guennec, M ; Butzkueven, H ; Tilson, H ; MacDonald, TM ; Hellwig, K (SAGE Publications, 2018)
    BACKGROUND AND METHODS: Limited data are available on the safety of fingolimod in pregnant women. We estimated the risk of adverse pregnancy outcomes in women with multiple sclerosis (MS) exposed to fingolimod either shortly before or during pregnancy in prospectively collected cases from clinical trials, observational studies, surveillance programs, and spontaneous reports. RESULTS: The prevalence of major malformations among live births does not appear to be significantly higher than those in the general population and the unexposed MS population. Similarly, the prevalence of cardiac malformations observed in this analysis was not significantly different from that of the general population. Proportions of miscarriage were in line with those of the general and unexposed MS population and no specific pattern of birth defects was identified. CONCLUSIONS: These data can help inform healthcare professionals and women with MS exposed to fingolimod during conception.
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    Assessment of Opicinumab in Acute Optic Neuritis Using Multifocal Visual Evoked Potential
    Klistorner, A ; Chai, Y ; Leocani, L ; Albrecht, P ; Aktas, O ; Butzkueven, H ; Ziemssen, T ; Ziemssen, F ; Frederiksen, J ; Xu, L ; Cadavid, D ; Butzkueven, H ; Garrick, R ; Vanopdenbosch, L ; Comi, G ; Dalmau, BS ; Andersson, M ; Plant, GT ; Matthews, T ; Williams, G (ADIS INT LTD, 2018-12)
    BACKGROUND: Multifocal visual evoked potential (MF-VEP) assesses a wider visual field than full-field VEP (FF-VEP) and potentially offers a more precise analysis of optic nerve injury and repair following optic neuritis. MF-VEP may offer advantages over FF-VEP as an endpoint in clinical trials of remyelinating therapies. OBJECTIVE: MF-VEP testing was used to study changes in visual pathways in 48% of RENEW [phase II, opicinumab (anti-LINGO-1; BIIB033) vs. placebo after first acute unilateral optic neuritis] participants. METHODS: This exploratory MF-VEP RENEW substudy compared mean outcomes at weeks 24 and 32 among participants in the intent-to-treat (ITT; n = 39; 72% female; mean age: 32.3 years) and per-protocol (PP; n = 31; 71% female; mean age: 32.2 years) populations in affected and fellow eye latency from fellow eye baseline latency and affected and fellow eye amplitude from their own baselines. Treatment differences were evaluated using analysis of covariance (week 24) and a mixed-effect model of repeated measures (week 32). Last observation carried forward was used to impute missing data at week 24. RESULTS: A trend for improvement in affected eye MF-VEP latency with opicinumab versus placebo was seen in the ITT and PP populations at weeks 24 and 32. Both treatment groups in the ITT population experienced partial recovery of amplitude in the affected eye at week 32. Notably, the mean change in fellow eye amplitude at weeks 24 and 32 was - 17.57 and - 31.41 nanovolts (nV) in placebo but only - 0.59 and 1.93 nV in the opicinumab group [differences at weeks 24 and 32: 16.98 nV (p = 0.050) and 33.33 nV (p < 0.01), respectively]. CONCLUSION: Results from this substudy showed advantages of MF-VEP over FF-VEP in multicenter studies of central nervous system reparative therapies and provide novel evidence that fellow eye visual pathway amplitude loss occurs after optic neuritis but can potentially be prevented by opicinumab treatment. REGISTRATION: ClinicalTrials.gov identifier NCT01721161.
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    Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects
    Patsopoulos, NA ; Barcellos, LF ; Hintzen, RQ ; Schaefer, C ; Van Duijn, CM ; Noble, JA ; Raj, T ; Gourraud, P-A ; Stranger, BE ; Oksenberg, J ; Olsson, T ; Taylor, BV ; Sawcer, S ; Hafler, DA ; Carrington, M ; De Jager, PL ; De Bakker, PIW ; Gibson, G (PUBLIC LIBRARY SCIENCE, 2013-11)
    The major histocompatibility complex (MHC) region is strongly associated with multiple sclerosis (MS) susceptibility. HLA-DRB1*15:01 has the strongest effect, and several other alleles have been reported at different levels of validation. Using SNP data from genome-wide studies, we imputed and tested classical alleles and amino acid polymorphisms in 8 classical human leukocyte antigen (HLA) genes in 5,091 cases and 9,595 controls. We identified 11 statistically independent effects overall: 6 HLA-DRB1 and one DPB1 alleles in class II, one HLA-A and two B alleles in class I, and one signal in a region spanning from MICB to LST1. This genomic segment does not contain any HLA class I or II genes and provides robust evidence for the involvement of a non-HLA risk allele within the MHC. Interestingly, this region contains the TNF gene, the cognate ligand of the well-validated TNFRSF1A MS susceptibility gene. The classical HLA effects can be explained to some extent by polymorphic amino acid positions in the peptide-binding grooves. This study dissects the independent effects in the MHC, a critical region for MS susceptibility that harbors multiple risk alleles.
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    CONTINUING FINGOLIMOD AFTER DEVELOPMENT OF MACULAR EDEMA: A CASE REPORT
    Li, V ; Kane, J ; Chan, HHL ; Hall, AJ ; Butzkueven, H (LIPPINCOTT WILLIAMS & WILKINS, 2014-08)