Publications by authors named "Jerry S Wolinsky"

115 Publications

Risk of requiring a wheelchair in primary progressive multiple sclerosis: Data from the ORATORIO trial and the MSBase registry.

Eur J Neurol 2021 Mar 16. Epub 2021 Mar 16.

McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.

Background: Reaching Expanded Disability Status Scale (EDSS) ≥7.0 represents the requirement for a wheelchair. Here we : (1) assess the effect of ocrelizumab on time to EDSS ≥7.0 over the ORATORIO (NCT01194570) double-blind and extended controlled periods (DBP+ECP); (2) quantify likely long-term benefits by extrapolating results; (3) assess the plausibility of extrapolations, using an independent real-world cohort (MSBase registry; ACTRN12605000455662).

Methods: Post-hoc analyses assessing time to 24-week confirmed EDSS ≥7.0 in two cohorts of patients with PPMS (baseline EDSS 3.0-6.5) were investigated, in ORATORIO and MSBase.

Results: In the ORATORIO DBP+ECP, ocrelizumab reduced the risk of 24-week confirmed EDSS ≥7.0 (hazard ratio=0.54, 95%CI: 0.31-0.92, P = 0.022). Extrapolated median time to 24-week confirmed EDSS ≥7.0 was 12.1 and 19.2 years for placebo and ocrelizumab, respectively (7.1-year delay [95%CI: -4.3-18.4]). In MSBase, the median time to 24-week confirmed EDSS ≥7.0 was 12.4 years.

Conclusion: Compared with placebo, ocrelizumab significantly delayed time to 24-week confirmed wheelchair requirement in ORATORIO. The plausibility of the extrapolated median time to reach this milestone in the placebo group was supported by observed real-world data from MSBase. Extrapolated benefits for ocrelizumab over placebo could represent a truly meaningful delay in loss of ambulation and independence.
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http://dx.doi.org/10.1111/ene.14824DOI Listing
March 2021

Time to walking aid after 6.5 years of ocrelizumab treatment in patients with relapsing multiple sclerosis: Data from the OPERA I and OPERA II trials.

Eur J Neurol 2021 Mar 16. Epub 2021 Mar 16.

McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.

Background: Requiring a walking aid is a fundamental milestone in MS, represented by Expanded Disability Status Scale (EDSS) score ≥6.0. Here we assess the effect of ocrelizumab on time to EDSS≥6.0 in relapsing MS.

Methods: Time to EDSS≥6.0 confirmed for ≥24 and ≥48 weeks was assessed over 6.5 years (336 weeks) in the double-blind and open-label extension periods of OPERA I (NCT01247324) and OPERA II (NCT01412333).

Results: Time to reach EDSS≥6.0 was significantly delayed in those initially randomized to ocrelizumab versus interferon. Over 6.5 years, the risk of requiring a walking aid confirmed for ≥24 weeks was 34% lower among those who initiated ocrelizumab earlier vs. delayed treatment (average HR DBP+OLE [95%CI]: 0.66 [0.45-0.95]; P = 0.024); the risk of requiring a walking aid confirmed for ≥48 weeks was 46% lower (average HR DBP+OLE [95%CI]: 0.54 [0.35-0.83]; P = 0.004).

Conclusion: The reduced risk of requiring a walking aid in earlier initiators of ocrelizumab demonstrates the long-term implications of earlier highly effective treatment.
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http://dx.doi.org/10.1111/ene.14823DOI Listing
March 2021

Safety and efficacy of MD1003 (high-dose biotin) in patients with progressive multiple sclerosis (SPI2): a randomised, double-blind, placebo-controlled, phase 3 trial.

Lancet Neurol 2020 12 23;19(12):988-997. Epub 2020 Oct 23.

Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Background: There is an unmet need to develop therapeutic interventions directed at the neurodegeneration that underlies progression in multiple sclerosis. High-dose, pharmaceutical-grade biotin (MD1003) might enhance neuronal and oligodendrocyte energetics, resulting in improved cell function, repair, or survival. The MS-SPI randomised, double-blind, placebo-controlled study found that MD1003 improved disability outcomes over 12 months in patients with progressive multiple sclerosis. The SPI2 study was designed to assess the safety and efficacy of MD1003 in progressive forms of multiple sclerosis in a larger, more representative patient cohort.

Methods: SPI2 was a randomised, double-blind, parallel-group, placebo-controlled trial done at 90 academic and community multiple sclerosis clinics across 13 countries. Patients were aged 18-65 years, had a diagnosis of primary or secondary progressive multiple sclerosis fulfilling the revised International Panel criteria and Lublin criteria, a Kurtzke pyramidal functional subscore of at least 2 (defined as minimal disability), an expanded disability status scale (EDSS) score of 3·5-6·5, a timed 25-foot walk (TW25) of less than 40 s, evidence of clinical disability progression, and no relapses in the 2 years before enrolment. Concomitant disease-modifying therapies were allowed. Patients were randomly assigned (1:1) by an independent statistician using an interactive web response system, with stratification by study site and disease history, to receive MD1003 (oral biotin 100 mg three times daily) or placebo. Participants, investigators, and assessors were masked to treatment assignment. The primary endpoint was a composite of the proportion of participants with confirmed improvement in EDSS or TW25 at month 12, confirmed at month 15, versus baseline. The primary endpoint was assessed in the intention-to-treat analysis set, after all participants completed the month 15 visit. Safety analyses included all participants who received at least one dose of MD1003. This trial is registered with ClinicalTrials.gov (NCT02936037) and the EudraCT database (2016-000700-29).

Findings: From Feb 22, 2017, to June 8, 2018, 642 participants were randomly assigned MD1003 (n=326) or placebo (n=316). The double-blind, placebo-controlled phase of the study ended when the primary endpoint for the last-entered participant was assessed on Nov 15, 2019. The mean time in the placebo-controlled phase was 20·1 months (SD 5·3; range 15-27). For the primary outcome, 39 (12%) of 326 patients in the MD1003 group compared with 29 (9%) of 316 in the placebo group improved at month 12, with confirmation at month 15 (odds ratio 1·35 [95% CI 0·81-2·26]). Treatment-emergent adverse events occurred in 277 (84%) of 331 participants in the MD1003 group and in 264 (85%) of 311 in the placebo group. 87 (26%) of 331 participants in the MD1003 group and 82 (26%) of 311 participants in the placebo group had at least one serious treatment-emergent adverse event. One (<1%) person died in the MD1003 group and there were no deaths in the placebo group. Despite use of mitigation strategies, MD1003 led to inaccurate laboratory results for tests using biotinylated antibodies.

Interpretation: This study showed that MD1003 did not significantly improve disability or walking speed in patients with progressive multiple sclerosis and thus, in addition to the potential of MD1003 for deleterious health consequences from interference of laboratory tests, MD1003 cannot be recommended for treatment of progressive multiple sclerosis.

Funding: MedDay Pharmaceuticals.
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http://dx.doi.org/10.1016/S1474-4422(20)30347-1DOI Listing
December 2020

An International Standardized Magnetic Resonance Imaging Protocol for Diagnosis and Follow-up of Patients with Multiple Sclerosis: Advocacy, Dissemination, and Implementation Strategies.

Int J MS Care 2020 Sep-Oct;22(5):226-232. Epub 2020 Oct 27.

Standardized magnetic resonance imaging (MRI) protocols are important for the diagnosis and monitoring of patients with multiple sclerosis (MS). The Consortium of Multiple Sclerosis Centers (CMSC) convened an international panel of MRI experts to review and update the current guidelines. The objective was to update the standardized MRI protocol and clinical guidelines for diagnosis and follow-up of MS and develop strategies for advocacy, dissemination, and implementation. Conference attendees included neurologists, radiologists, technologists, and imaging scientists with expertise in MS. Representatives from the CMSC, Magnetic Resonance Imaging in MS (MAGNIMS), North American Imaging in Multiple Sclerosis Cooperative, US Department of Veteran Affairs, National Multiple Sclerosis Society, Multiple Sclerosis Association of America, MRI manufacturers, and commercial image analysis companies were present. Before the meeting, CMSC members were surveyed about standardized MRI protocols, gadolinium use, need for diffusion-weighted imaging, and the central vein sign. The panel worked to make the CMSC and MAGNIMS MRI protocols similar so that the updated guidelines could ultimately be accepted by international consensus. Advocacy efforts will promote the importance of standardized MS MRI protocols. Dissemination will include publications, meeting abstracts, educational programming, webinars, "meet the expert" teleconferences, and examination cards. Implementation will require comprehensive and coordinated efforts to make the protocol easy to access and use. The ultimate vision, and goal, is for the guidelines to be universally useful, usable, and used as the standard of care for patients with MS.
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http://dx.doi.org/10.7224/1537-2073.2020-094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643842PMC
October 2020

Long-term follow-up from the ORATORIO trial of ocrelizumab for primary progressive multiple sclerosis: a post-hoc analysis from the ongoing open-label extension of the randomised, placebo-controlled, phase 3 trial.

Lancet Neurol 2020 12 29;19(12):998-1009. Epub 2020 Oct 29.

Department of Neurology, University of California, San Francisco, CA, USA.

Background: The safety and efficacy of ocrelizumab in primary progressive multiple sclerosis were shown in the phase 3 ORATORIO trial. In this study, we assessed the effects of maintaining or switching to ocrelizumab therapy on measures of disease progression and safety in the open-label extension phase of ORATORIO.

Methods: ORATORIO was an international, multicentre, double-blind, randomised, placebo-controlled, phase 3 trial done at 182 study locations including academic centres, hospitals, and community speciality centres within 29 countries across the Americas, Australia, Europe, Israel, New Zealand, and Russia. Patients with primary progressive multiple sclerosis aged 18-55 years who had an Expanded Disability Status Scale (EDSS) score of 3·0-6·5 were eligible for enrolment. Those who had previous treatment with B-cell-targeted therapies or other immunosuppressive medications were excluded. Eligible participants were randomly assigned (2:1) to receive either intravenous infusion of 600 mg of ocrelizumab (two 300 mg infusions 14 days apart) or placebo every 24 weeks for at least 120 weeks until a prespecified number (n=253) of disability events occurred. After the double-blind phase, patients entered an extended controlled period of variable duration, during which they and investigators became aware of treatment allocation. Following this period, patients could enter an optional open-label extension, during which they continued ocrelizumab or switched from placebo to ocrelizumab. Time to onset of disability progression was confirmed at 24 weeks with four measures (ie, increase in EDSS score, ≥20% increase in time to complete the 9-Hole Peg Test [9HPT], ≥20% increase in time to perform the Timed 25-Foot Walk [T25FW], and composite progression defined as the first confirmed occurrence of any of these three individual measures), as was time to requiring a wheelchair (EDSS ≥7). Conventional MRI measures were also analysed. The intention-to-treat population was used for the safety and efficacy analyses; all analyses, and their timings, were done post hoc. ORATORIO is registered with ClinicalTrials.gov, NCT01194570, and is ongoing.

Findings: From March 3, 2011, to Dec 27, 2012, 488 patients were randomly assigned to the ocrelizumab group and 244 to the placebo group. The extended controlled period started on July 24, 2015, and ended on April 27, 2016, when the last patient entered the open-label extension. Overall, 544 (74%) of 732 participants completed the double-blind period to week 144; 527 (97%) of 544 entered the open-label extension phase, of whom 451 (86%) are ongoing in the open-label extension. After at least 6·5 study years (48 weeks per study year) of follow-up, the proportion of patients with progression on disability measures was lower in those who initiated ocrelizumab early than in those initially receiving placebo for most of the measures of 24-week confirmed disability progression: EDSS, 51·7% vs 64·8% (difference 13·1% [95% CI 4·9-21·3]; p=0·0018); 9HPT, 30·6% vs 43·1% (12·5% [4·1-20·9]); p=0·0035); T25FW, 63·2% vs 70·7% (7·5% [-0·3 to 15·2]; p=0·058); composite progression, 73·2% vs 83·3% (10·1% [3·6-16·6]; p=0·0023); and confirmed time to requiring a wheelchair, 11·5% vs 18·9% (7·4% [0·8-13·9]; p=0·0274). At study end, the percentage change from baseline was lower in those who initiated ocrelizumab early than in those initially receiving placebo for T2 lesion volume (0·45% vs 13·00%, p<0·0001) and T1 hypointense lesion volume (36·68% vs 60·93%, p<0·0001). Over the entire period, in the ORATORIO all ocrelizumab exposure population, the rate of adverse events was 238·09 (95% CI 232·71-243·57) per 100 patient-years and serious adverse events was 12·63 (95% CI 11·41-13·94) per 100 patient-years; the most common serious adverse events were infections at 4·13 (95% CI 3·45-4·91) per 100 patient-years. No new safety signals emerged compared with the double-blind phase of ORATORIO.

Interpretation: Compared with patients switching from placebo, earlier and continuous ocrelizumab treatment provided sustained benefits on measures of disease progression over the 6·5 study years of follow-up. Although this study shows the benefit of earlier intervention with ocrelizumab in primary progressive disease, progression remains an important unmet need in multiple sclerosis. Further research should focus on how the potential benefits described in this study might be improved upon, particularly over longer time periods.

Funding: F Hoffmann-La Roche.
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http://dx.doi.org/10.1016/S1474-4422(20)30342-2DOI Listing
December 2020

Treatment Response Score to Glatiramer Acetate or Interferon Beta-1a.

Neurology 2021 01 6;96(2):e214-e227. Epub 2020 Oct 6.

From the Department of Health Sciences (DISSAL) (F.B., M.P.S.), University of Genoa, Italy; CORe (T.K., C.M.), Department of Medicine, University of Melbourne, Australia; Department of Neurology (F.L.), Icahn School of Medicine at Mount Sinai, New York, NY; Department of Biostatistics (G.C.), University of Alabama at Birmingham; Department of Neurology and Center for Clinical Neuroscience (D.H., E.K.H.), First Medical Faculty, Charles University, Prague, Czech Republic; Department of Basic Medical Sciences, Neuroscience and Sense Organs (M. Trojano), University of Bari, Italy; Department of Neuroscience (A.P., M.G., P.D.), Faculty of Medicine, Université de Montréal, Quebec, Canada; Department of Neuroscience, Imaging, and Clinical Sciences (M.O.), University G. d'Annunzio, Chieti; IRCCS Istituto delle Scienze Neurologiche di Bologna (A.L.); Dipartimento di Scienze Biomediche e Neuromotorie (A.L.), Università di Bologna, Italy; Hospital Universitario Virgen Macarena (G. Izquierdo. S.E.), Sevilla, Spain; Department of Medical, Surgical Science and Advanced Technology "GF Ingrassia" (F.P.), University of Catania, Italy; Ondokuz Mayis University (M. Terzi), Department of Neurology, Samsun, Turkey; CISSS Chaudi're-Appalache (P.G.), Centre-Hospitalier, Levis, Quebec, Canada; IRCCS Mondino Foundation (R.B.), Pavia; Department of Neuroscience (P.S., D.F.), Azienda Ospedaliera Universitaria, Modena, Italy; Department of Neurology (S.O.), Dokuz Eylul University, Izmir, Turkey; Ospedali Riuniti di Salerno (G. Iuliano), Salerno, Italy; Department of Neurology (C.B.), Karadeniz Technical University, Trabzon, Turkey; Department of Neurology (R.H.), Zuyderland Medical Center, Sittard, the Netherlands; Neuro Rive-Sud (F.G.), Hôpital Charles LeMoyne, Greenfield Park, Quebec, Canada; Clinico San Carlos (C.O.-G), Madrid, Spain; Cliniques Universitaires Saint-Luc (V.v.P.); Université Catholique de Louvain (V.v.P.), Brussels, Belgium; UOC Neurologia (E.C.), Azienda Sanitaria Unica Regionale Marche-AV3, Macerata, Italy; Kommunehospitalet (T.P.), Arhus C, Denmark; Koc University (A.A.), School of Medicine; Bakirkoy Education and Research Hospital for Psychiatric and Neurological Diseases (A.S.), Istanbul, Turkey; Hospital Germans Trias i Pujol (C.R.-T.), Badalona, Spain; University of Queensland (P.M.), Brisbane, Australia; Haydarpasa Numune Training and Research Hospital (R.T.), Istanbul, Turkey; Central Clinical School (H.B.), Monash University, Melbourne, Australia; The University of Texas Health Science Center at Houston (J.S.W.); Rehabilitation Unit (C.S.), "Mons. L. Novarese" Hospital, Moncrivello; and IRCCS Ospedale Policlinico San Martino (M.P.S.), Genoa, Italy.

Objective: To compare the effectiveness of glatiramer acetate (GA) vs intramuscular interferon beta-1a (IFN-β-1a), we applied a previously published statistical method aimed at identifying patients' profiles associated with efficacy of treatments.

Methods: Data from 2 independent multiple sclerosis datasets, a randomized study (the Combination Therapy in Patients With Relapsing-Remitting Multiple Sclerosis [CombiRx] trial, evaluating GA vs IFN-β-1a) and an observational cohort extracted from MSBase, were used to build and validate a treatment response score, regressing annualized relapse rates (ARRs) on a set of baseline predictors.

Results: The overall ARR ratio of GA to IFN-β-1a in the CombiRx trial was 0.72. The response score (made up of a linear combination of age, sex, relapses in the previous year, disease duration, and Expanded Disability Status Scale score) detected differential response of GA vs IFN-β-1a: in the trial, patients with the largest benefit from GA vs IFN-β-1a (lower score quartile) had an ARR ratio of 0.40 (95% confidence interval [CI] 0.25-0.63), those in the 2 middle quartiles of 0.90 (95% CI 0.61-1.34), and those in the upper quartile of 1.14 (95% CI 0.59-2.18) (heterogeneity = 0.012); this result was validated on MSBase, with the corresponding ARR ratios of 0.58 (95% CI 0.46-0.72), 0.92 (95% CI 0.77-1.09,) and 1.29 (95% CI 0.97-1.71); heterogeneity < 0.0001).

Conclusions: We demonstrate the possibility of a criterion, based on patients' characteristics, to choose whether to treat with GA or IFN-β-1a. This result, replicated on an independent real-life cohort, may have implications for clinical decisions in everyday clinical practice.
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http://dx.doi.org/10.1212/WNL.0000000000010991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905777PMC
January 2021

Assessment of Racial/Ethnic Disparities in Volumetric MRI Correlates of Clinical Disability in Multiple Sclerosis: A Preliminary Study.

J Neuroimaging 2021 Jan 19;31(1):115-123. Epub 2020 Sep 19.

Division of Multiple Sclerosis and Neuroimmunology, Department of Neurology, McGovern Medical School (UT Health), University of Texas Health Science Center at Houston, Houston, TX.

Background And Purpose: Although global and regional brain volume has been established as a relevant measure to define and predict multiple sclerosis (MS) severity, characterization of specific trends by race/ethnicity is currently lacking. We aim to (1) characterize racial disparities in disability-specific patterns of brain MRI volumetric measures between Hispanic and Caucasian individuals with MS and (2) explore the relevance of these measures as predictors of clinical disability progression.

Methods: Brain MRI scans from 94 Hispanic and 94 age- and gender-matched Caucasian MS patients were analyzed using automatic and manual segmentation techniques. Select global and regional volume measures were correlated to Expanded Disability Status Scale (EDSS) scores at baseline and subsequent follow-up visits.

Results: Hispanic patients had a higher baseline median EDSS score (interquartile range [IQR], 2.0; [1.0-3.5]) compared to Caucasians (median [IQR], 1.0 [.0-2.0]) and an increased risk of requiring ambulatory assistance (hazard ratio [HR], 9.7; 95% confidence interval [CI], 2.8-32.5). Normalized thalamic volume was moderately associated with EDSS scores (r   = -.42,  P < .001 in Hispanics; r   = -.32, P  = .002 in Caucasians) and was the best predictor of sustained disability worsening in both racial groups in a time-to-event analysis.

Conclusions: The confounding impact of race on quantitative brain volume measures may affect the interpretation of outcome measures in MS clinical trials.
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http://dx.doi.org/10.1111/jon.12788DOI Listing
January 2021

Long-term safety and efficacy of teriflunomide in patients with relapsing multiple sclerosis: Results from the TOWER extension study.

Mult Scler Relat Disord 2020 Nov 1;46:102438. Epub 2020 Aug 1.

The Ottawa Hospital Ontario, 501 Smyth Road, Box 601, Ottawa, ON, Canada.

Background: In the phase 3 TOWER core study (NCT00751881), the efficacy and safety of teriflunomide compared with placebo were demonstrated in patients with relapsing forms of multiple sclerosis (RMS). Here, the long-term safety and efficacy outcomes from the TOWER extension study (NCT00751881) are reported.

Methods: All patients who entered the extension (N = 751) were assigned to teriflunomide 14 mg and assessed for long-term safety and efficacy.

Results: Of 751 patients in the TOWER extension study, 253, 265, and 233 patients received placebo/teriflunomide 14 mg, teriflunomide 7 mg/14 mg, and teriflunomide 14 mg/14 mg, respectively. Median teriflunomide exposure was 4.25 years (maximum 6.3 years). The overall frequency of adverse events (AEs) was comparable across treatment groups, but a higher proportion of patients in the teriflunomide 7 mg/14 mg (12.4%) and 14 mg/14 mg (12.4%) groups had serious AEs compared with the placebo/teriflunomide 14 mg group (6.4%). Alanine aminotransferase increase and hair thinning occurred at a higher frequency in the placebo/teriflunomide 14 mg group (11.2% and 14.3%, respectively) compared with the teriflunomide 7 mg/14 mg (3.0% and 4.5%, respectively) and 14 mg/14 mg groups (5.2% and 4.3%, respectively). The incidences of AEs of interest (hematologic and hepatic effects, peripheral neuropathy, hypertension, and malignancy) were low and comparable across treatment arms. Disability worsening and adjusted annualized relapse rates were low and stable over time, and mean Expanded Disability Status Scale scores were unchanged over time, for all treatment groups.

Conclusion: In the TOWER extension study, the efficacy of teriflunomide 14 mg was maintained in patients with RMS. No new or unexpected AEs were observed with teriflunomide treatment, supporting a safety profile in the extension that was consistent with the core trial. These findings support the positive benefit:risk profile of teriflunomide as a long-term immunomodulatory therapy.
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http://dx.doi.org/10.1016/j.msard.2020.102438DOI Listing
November 2020

Five years of ocrelizumab in relapsing multiple sclerosis: OPERA studies open-label extension.

Neurology 2020 09 20;95(13):e1854-e1867. Epub 2020 Jul 20.

From the Department of Neurology (S.L.H.), University of California, San Francisco; Neurologic Clinic and Policlinic (L.K.), Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital Basel, University of Basel, Switzerland; NeuroRx Research (D.L.A.); Departments of Neurology and Neurosurgery (D.L.A.), McGill University, Montreal, Canada; Department of Neurology and Center for Neuroinflammation and Experimental Therapeutics (A.B.-O.), University of Pennsylvania, Philadelphia; Department of Neurology (B.B.), CHU de Bordeaux, France; Department of Neurology (R.T.N.), Washington University School of Medicine, St. Louis, MO; Division of Neurology (A.T.), Department of Medicine, University of British Columbia, Vancouver, Canada; Department of Neurology (J.S.W.), McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth); F. Hoffmann-La Roche Ltd (S.B., H.K., M.M., F.M., S.H.), Basel, Switzerland; Genentech, Inc. (V.L., L.M.), South San Francisco, CA; Division of Neurology (X.M.), University of Toronto, Canada; and Department of Neurology-Neuroimmunology (X.M.), Vall d'Hebron University Hospital, Barcelona, Spain. During completion of the work related to this article, S.B. and L.M. were employees of F. Hoffmann-La Roche Ltd; current affiliations are Biogen (S.B.), Cambridge, MA; and Alder Biopharmaceuticals Inc. (L.M.), Bothell, WA.

Objective: To assess over 3 years of follow-up the effects of maintaining or switching to ocrelizumab (OCR) therapy on clinical and MRI outcomes and safety measures in the open-label extension (OLE) phase of the pooled OPERA: I/II studies in relapsing multiple sclerosis.

Methods: After 2 years of double-blind, controlled treatment, patients continued OCR (600 mg infusions every 24 weeks) or switched from interferon (IFN)-β-1a (44 μg 3 times weekly) to OCR when entering the OLE phase (3 years). Adjusted annualized relapse rate, time to onset of 24-week confirmed disability progression (CDP)/improvement (CDP), brain MRI activity (gadolinium-enhanced and new/enlarging T2 lesions), and percentage brain volume change were analyzed.

Results: Of patients entering the OLE phase, 88.6% completed year 5. The cumulative proportion with 24-week CDP was lower in patients who initiated OCR earlier vs patients initially receiving IFN-β-1a (16.1% vs 21.3% at year 5; = 0.014). Patients continuing OCR maintained and those switching from IFN-β-1a to OCR attained near complete and sustained suppression of new brain MRI lesion activity from years 3-5. Over the OLE phase, patients continuing OCR exhibited less whole brain volume loss from double-blind study baseline vs those switching from IFN-β-1a (-1.87% vs -2.15% at year 5; < 0.01). Adverse events were consistent with past reports and no new safety signals emerged with prolonged treatment.

Conclusion: Compared with patients switching from IFN-β-1a, earlier and continuous OCR treatment up to 5 years provided sustained benefit on clinical and MRI measures of disease progression.

Classification Of Evidence: This study provides Class III evidence that earlier and continuous treatment with OCR provided sustained benefit on clinical and MRI outcomes of disease activity and progression compared with patients switching from IFN-β-1a. The study is rated Class III because of the initial treatment randomization disclosure that occurred after inclusion in OLE.

Clinical Trial Identifiers: NCT01247324/NCT01412333.
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http://dx.doi.org/10.1212/WNL.0000000000010376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682822PMC
September 2020

Temporal profile of lymphocyte counts and relationship with infections with fingolimod therapy in paediatric patients with multiple sclerosis: Results from the PARADIG study.

Mult Scler 2020 Jul 7:1352458520936934. Epub 2020 Jul 7.

Division of Paediatric Neurology, Department of Paediatrics and Adolescent Medicine, University Medical Centre Göttingen, Georg August University Göttingen, Göttingen, Germany.

Background: Reduction in absolute lymphocyte count (ALC) is expected with fingolimod treatment.

Objective: To evaluate the effect of fingolimod 0.5 mg versus intramuscular interferon β-1a (30 μg) on ALC and its relationship with infections in paediatric-onset multiple sclerosis (POMS) up to 4 years.

Methods: We assessed ALC at baseline, monthly till 3 months, and every 3 months (core phase) and with variable periodicity (extension phase) of Phase 3 PARADIG study ( = 215). Incidence rates (IRs) of infection-related adverse events (AEs)/100 patient-years were analysed by on-study nadir ALC.

Results: With fingolimod, ALC rapidly reduced to 29.9%-34.4% of baseline values within 2 weeks and remained stable thereafter; no relevant changes observed with interferon. IRs of AEs were 67.6 with fingolimod and 61.8 with interferon; IR ratios with respect to interferon, overall: 1.09, by nadir ALC 0.2-0.4 × 10/L: 1.13 and >0.4 × 10/L: 0.91. Three patients had a single episode of ALC <0.2 × 10/L (core phase). No opportunistic infections were observed and infection risk did not increase during the extension phase.

Conclusion: In paediatric patients, the overall incidence of infections was comparable between fingolimod and interferon. No association was observed between nadir ALC and infections in POMS, although sample size may have been too small to rule an association.
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http://dx.doi.org/10.1177/1352458520936934DOI Listing
July 2020

Contribution of Relapse-Independent Progression vs Relapse-Associated Worsening to Overall Confirmed Disability Accumulation in Typical Relapsing Multiple Sclerosis in a Pooled Analysis of 2 Randomized Clinical Trials.

JAMA Neurol 2020 09;77(9):1132-1140

Weill Institute for Neurosciences, University of California, San Francisco, San Francisco.

Importance: Accumulation of disability in multiple sclerosis may occur as relapse-associated worsening (RAW) or steady progression independent of relapse activity (PIRA), with PIRA regarded as a feature of primary and secondary progressive multiple sclerosis.

Objective: To investigate the contributions of relapse-associated worsening vs relapse-independent progression to overall confirmed disability accumulation (CDA) and assess respective baseline prognostic factors and outcomes of 2 treatments.

Design, Setting, And Participants: Analyses occurred from July 2015 to February 2020 on pooled data from the intention-to-treat population of 2 identical, phase 3, multicenter, double-blind, double-dummy, parallel-group randomized clinical trials (OPERA I and II) conducted between August 2011 and April 2015. In the trials, patients with relapsing multiple sclerosis (RMS), diagnosed using the 2010 revised McDonald criteria, were randomized from 307 trial sites in 56 countries; resulting data were analyzed in the pooled data set.

Interventions: Participants were randomized 1:1 to receive 600 mg of ocrelizumab by intravenous infusion every 24 weeks or subcutaneous interferon β-1a 3 times a week at a dose of 44 μg throughout a 96-week treatment period.

Main Outcomes And Measures: Confirmed disability accumulation was defined by an increase in 1 or more of 3 measures (Expanded Disability Status Scale, timed 25-ft walk, or 9-hole peg test), confirmed after 3 or 6 months, and classified per temporal association with confirmed clinical relapses (PIRA or RAW).

Results: In the pooled OPERA I and II population (1656 of 2096 eligible participants), baseline demographics and disease characteristics were similar for patients randomized to interferon β-1a vs ocrelizumab (mean [SD] age, 37.2 [9.2] vs 37.1 [9.2] years; 552 [66.6%] vs 541 women [65.4%]). After 96 weeks, 12-week composite CDA had occurred in 223 (29.6% by Kaplan-Meier estimate) randomized to interferon β-1a and 167 (21.1%) randomized to ocrelizumab; 24-week composite CDA had occurred in 170 (22.7%) taking interferon β-1a and 129 (16.2%) taking ocrelizumab. The PIRA events were the main contributors to 12-week and 24-week composite CDA after 96 weeks in patients treated with interferon β-1a (174 of 223 [78.0%] and 137 of 170 [80.6%], respectively) and ocrelizumab (147 of 167 [88.0%] and 115 of 129 [89.1%], respectively); a minority had CDA explained by RAW events (69 of 390 [17.7%] and 52 of 299 [17.4%], respectively). Very few patients with composite CDA experienced both RAW and PIRA events (17 of 390 [4.4%] for 12-week and 15 of 299 [5.0%] for 24-week composite CDA). Ocrelizumab (vs interferon β-1a) was associated with reduced risk of composite CDA (hazard ratio [HR], 0.67) and confirmed PIRA (HR, 0.78) and RAW (HR, 0.47) events.

Conclusions And Relevance: Most disability accumulation in RMS is not associated with overt relapses. This indicates an underlying progression in this typical RMS population and challenges the current clinical distinction of relapsing and progressive forms of multiple sclerosis. Ocrelizumab was superior to interferon β-1a in preventing both RAW and PIRA.

Trial Registration: ClinicalTrials.gov Identifiers: OPERA I (NCT01247324) and OPERA II (NCT01412333).
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http://dx.doi.org/10.1001/jamaneurol.2020.1568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281382PMC
September 2020

An exploratory analysis of the efficacy of ocrelizumab in patients with multiple sclerosis with increased disability.

Mult Scler J Exp Transl Clin 2020 Jan-Mar;6(1):2055217320911939. Epub 2020 Mar 16.

Central Texas Neurology Consultants, Round Rock, TX, USA.

Background: Ocrelizumab, an anti-CD20 humanized monoclonal antibody, reduced disease progression in pivotal trials of patients with relapsing (OPERA I, OPERA II) and primary progressive (ORATORIO) multiple sclerosis (MS). These effects may be particularly important among patients with increased disability.

Objective: In this post hoc exploratory analysis, we evaluated the efficacy of ocrelizumab on disability progression among a subgroup of patients with MS who had increased baseline disability levels (Expanded Disability Status Scale scores ≥4.0) in the pivotal trials.

Methods: During the double-blind period, patients received ocrelizumab 600 mg intravenously every 24 weeks for 96 weeks in the OPERA trials (versus interferon β-1a 44 μg subcutaneously three times per week) and for 120 weeks in ORATORIO (versus placebo). Kaplan-Meier and Cox survival analyses were used to assess disability outcome measures.

Results: Baseline demographic, disease, and treatment characteristics were generally comparable across treatment groups in patients with increased disability from the OPERA and ORATORIO trials. Ocrelizumab treatment numerically, and in some instances significantly, reduced confirmed disability progression versus the comparator in these patients.

Conclusions: In patients with increased baseline disability, ocrelizumab reduced the risk of confirmed disability progression versus interferon β-1a in patients with relapsing-onset MS and versus placebo in patients with progression-onset MS.
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http://dx.doi.org/10.1177/2055217320911939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079307PMC
March 2020

Effect of fingolimod on MRI outcomes in patients with paediatric-onset multiple sclerosis: results from the phase 3 PARADIG study.

J Neurol Neurosurg Psychiatry 2020 05 4;91(5):483-492. Epub 2020 Mar 4.

Partners Pediatric Multiple Sclerosis Center, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.

Objective: PARADIG demonstrated superior efficacy and comparable safety of fingolimod versus interferon β-1a (IFN β-1a) in paediatric-onset multiple sclerosis (PoMS). This study aimed to report all predefined MRI outcomes from this study.

Methods: Patients with multiple sclerosis (MS) (aged 10-<18 years) were randomised to once-daily oral fingolimod (n=107) or once-weekly intramuscular IFN β-1a (n=108) in this flexible duration study. MRI was performed at baseline and every 6 months for up to 2 years or end of the study (EOS) in case of early treatment discontinuation/completion. Key MRI endpoints included the annualised rate of formation of new/newly enlarging T2 lesions, gadolinium-enhancing (Gd+) T1 lesions, new T1 hypointense lesions and combined unique active (CUA) lesions (6 months onward), changes in T2 and Gd+ T1 lesion volumes and annualised rate of brain atrophy (ARBA).

Results: Of the randomised patients, 107 each were treated with fingolimod and IFN β-1a for up to 2 years. Fingolimod reduced the annualised rate of formation of new/newly enlarging T2 lesions (52.6%, p<0.001), number of Gd+ T1 lesions per scan (66.0%, p<0.001), annualised rate of new T1 hypointense lesions (62.8%, p<0.001) and CUA lesions per scan (60.7%, p<0.001) versus IFN β-1a at EOS. The percent increases from baseline in T2 (18.4% vs 32.4%, p<0.001) and Gd+ T1 (-72.3% vs 4.9%, p=0.001) lesion volumes and ARBA (-0.48% vs -0.80%, p=0.014) were lower with fingolimod versus IFN β-1a, the latter partially due to accelerated atrophy in the IFN β-1a group.

Conclusion: Fingolimod significantly reduced MRI activity and ARBA for up to 2 years versus IFN β-1a in PoMS.
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http://dx.doi.org/10.1136/jnnp-2019-322138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231437PMC
May 2020

Diroximel Fumarate Demonstrates an Improved Gastrointestinal Tolerability Profile Compared with Dimethyl Fumarate in Patients with Relapsing-Remitting Multiple Sclerosis: Results from the Randomized, Double-Blind, Phase III EVOLVE-MS-2 Study.

CNS Drugs 2020 02;34(2):185-196

Department of Neurology, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.

Background: Diroximel fumarate (DRF) is a novel oral fumarate approved in the USA for relapsing forms of multiple sclerosis. DRF is converted to monomethyl fumarate, the pharmacologically active metabolite of dimethyl fumarate (DMF). DRF 462 mg and DMF 240 mg produce bioequivalent exposure of monomethyl fumarate and are therefore expected to have similar efficacy/safety profiles; the distinct chemical structure of DRF may contribute to its tolerability profile.

Objectives: The objective of this study was to compare the gastrointestinal tolerability of DRF and DMF over 5 weeks in patients with relapsing-remitting multiple sclerosis.

Methods: EVOLVE-MS-2 was a phase III, randomized, double-blind, head-to-head, 5-week study evaluating the gastrointestinal tolerability of DRF 462 mg vs DMF 240 mg, administered twice daily in patients with relapsing-remitting multiple sclerosis, using two self-administered gastrointestinal symptom scales: Individual Gastrointestinal Symptom and Impact Scale (IGISIS) and Global Gastrointestinal Symptom and Impact Scale (GGISIS). The primary endpoint was the number of days with an IGISIS intensity score ≥ 2 relative to exposure. Other endpoints included the degree of gastrointestinal symptom severity measured by IGISIS/GGISIS and assessment of safety/tolerability.

Results: DRF-treated patients experienced a statistically significant reduction (46%) in the number of days with an IGISIS symptom intensity score ≥ 2 compared with DMF-treated patients (rate ratio [95% confidence interval]: 0.54 [0.39-0.75]; p = 0.0003). Lower rates of gastrointestinal adverse events (including diarrhea, nausea, vomiting, and abdominal pain) were observed with DRF than DMF (34.8% vs 49.0%). Fewer patients discontinued DRF than DMF because of adverse events (1.6% vs 5.6%) and gastrointestinal adverse events (0.8% vs 4.8%).

Conclusions: DRF demonstrated an improved gastrointestinal tolerability profile compared with DMF, with less severe gastrointestinal events and fewer days of self-assessed gastrointestinal symptoms, fewer gastrointestinal adverse events, and lower discontinuation rates because of gastrointestinal adverse events.

Clinical Trials Registration: ClinicalTrials.gov (NCT03093324).
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http://dx.doi.org/10.1007/s40263-020-00700-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018784PMC
February 2020

Deep Learning for Predicting Enhancing Lesions in Multiple Sclerosis from Noncontrast MRI.

Radiology 2020 02 17;294(2):398-404. Epub 2019 Dec 17.

From the Departments of Diagnostic and Interventional Imaging (P.A.N., I.C., S.J.S., R.E.G.) and Neurology (J.S.W.), McGovern Medical School, University of Texas Health Science Center, 6431 Fannin St, Houston, TX 77030; and Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574 (F.D.L.).

Background Enhancing lesions on MRI scans obtained after contrast material administration are commonly thought to represent disease activity in multiple sclerosis (MS); it is desirable to develop methods that can predict enhancing lesions without the use of contrast material. Purpose To evaluate whether deep learning can predict enhancing lesions on MRI scans obtained without the use of contrast material. Materials and Methods This study involved prospective analysis of existing MRI data. A convolutional neural network was used for classification of enhancing lesions on unenhanced MRI scans. This classification was performed for each slice, and the slice scores were combined by using a fully connected network to produce participant-wise predictions. The network input consisted of 1970 multiparametric MRI scans from 1008 patients recruited from 2005 to 2009. Enhanced lesions on postcontrast T1-weighted images served as the ground truth. The network performance was assessed by using fivefold cross-validation. Statistical analysis of the network performance included calculation of lesion detection rates and areas under the receiver operating characteristic curve (AUCs). Results MRI scans from 1008 participants (mean age, 37.7 years ± 9.7; 730 women) were analyzed. At least one enhancing lesion was observed in 519 participants. The sensitivity and specificity averaged across the five test sets were 78% ± 4.3 and 73% ± 2.7, respectively, for slice-wise prediction. The corresponding participant-wise values were 72% ± 9.0 and 70% ± 6.3. The diagnostic performances (AUCs) were 0.82 ± 0.02 and 0.75 ± 0.03 for slice-wise and participant-wise enhancement prediction, respectively. Conclusion Deep learning used with conventional MRI identified enhanced lesions in multiple sclerosis from images from unenhanced multiparametric MRI with moderate to high accuracy. © RSNA, 2019.
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http://dx.doi.org/10.1148/radiol.2019191061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980901PMC
February 2020

Diroximel fumarate (DRF) in patients with relapsing-remitting multiple sclerosis: Interim safety and efficacy results from the phase 3 EVOLVE-MS-1 study.

Mult Scler 2020 11 4;26(13):1729-1739. Epub 2019 Nov 4.

Alkermes Inc, Waltham, MA, USA.

Background: Diroximel fumarate (DRF) is a novel oral fumarate for patients with relapsing-remitting multiple sclerosis (RRMS). DRF and the approved drug dimethyl fumarate yield bioequivalent exposure to the active metabolite monomethyl fumarate; thus, efficacy/safety profiles are expected to be similar. However, DRF's distinct chemical structure may result in a differentiated gastrointestinal (GI) tolerability profile.

Objective: To report interim safety/efficacy findings from patients in the ongoing EVOLVE-MS-1 study.

Methods: EVOLVE-MS-1 is an ongoing, open-label, 96-week, phase 3 study assessing DRF safety, tolerability, and efficacy in RRMS patients. Primary endpoint is safety and tolerability; efficacy endpoints are exploratory.

Results: As of March 2018, 696 patients were enrolled; median exposure was 59.9 (range: 0.1-98.9) weeks. Adverse events (AEs) occurred in 84.6% (589/696) of patients; the majority were mild (31.2%; 217/696) or moderate (46.8%; 326/696) in severity. Overall treatment discontinuation was 14.9%; 6.3% due to AEs and <1% due to GI AEs. At Week 48, mean number of gadolinium-enhancing lesions was significantly reduced from baseline (77%;  < 0.0001) and adjusted annualized relapse rate was low (0.16; 95% confidence interval: 0.13-0.20).

Conclusion: Interim data from EVOLVE-MS-1 suggest DRF is a well-tolerated treatment with a favorable safety/efficacy profile for patients with RRMS.
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http://dx.doi.org/10.1177/1352458519881761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604551PMC
November 2020

Are multi-contrast magnetic resonance images necessary for segmenting multiple sclerosis brains? A large cohort study based on deep learning.

Magn Reson Imaging 2020 01 25;65:8-14. Epub 2019 Oct 25.

Department of Diagnostic and Interventional Imaging, McGovern Medical School, University of Texas Health Science Center, Houston, TX 77030, United States of America.

Background: Magnetic resonance images with multiple contrasts or sequences are commonly used for segmenting brain tissues, including lesions, in multiple sclerosis (MS). However, acquisition of images with multiple contrasts increases the scan time and complexity of the analysis, possibly introducing factors that could compromise segmentation quality.

Objective: To investigate the effect of various combinations of multi-contrast images as input on the segmented volumes of gray (GM) and white matter (WM), cerebrospinal fluid (CSF), and lesions using a deep neural network.

Methods: U-net, a fully convolutional neural network was used to automatically segment GM, WM, CSF, and lesions in 1000 MS patients. The input to the network consisted of 15 combinations of FLAIR, T1-, T2-, and proton density-weighted images. The Dice similarity coefficient (DSC) was evaluated to assess the segmentation performance. For lesions, true positive rate (TPR) and false positive rate (FPR) were also evaluated. In addition, the effect of lesion size on lesion segmentation was investigated.

Results: Highest DSC was observed for all the tissue volumes, including lesions, when the input was combination of all four image contrasts. All other input combinations that included FLAIR also provided high DSC for all tissue classes. However, the quality of lesion segmentation showed strong dependence on the input images. The DSC and TPR values for inputs with the four contrast combination and FLAIR alone were very similar, but FLAIR showed a moderately higher FPR for lesion size <100 μl. For lesions smaller than 20 μl all image combinations resulted in poor performance. The segmentation quality improved with lesion size.

Conclusions: Best performance for segmented tissue volumes was obtained with all four image contrasts as the input, and comparable performance was attainable with FLAIR only as the input, albeit with a moderate increase in FPR for small lesions. This implies that acquisition of only FLAIR images provides satisfactory tissue segmentation. Lesion segmentation was poor for very small lesions and improved rapidly with lesion size.
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http://dx.doi.org/10.1016/j.mri.2019.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918476PMC
January 2020

Deep-Learning-Based Neural Tissue Segmentation of MRI in Multiple Sclerosis: Effect of Training Set Size.

J Magn Reson Imaging 2020 05 18;51(5):1487-1496. Epub 2019 Oct 18.

Department of Diagnostic and Interventional Imaging, McGovern Medical School, University of Texas Health Science Center, Houston, Texas, USA.

Background: The dependence of deep-learning (DL)-based segmentation accuracy of brain MRI on the training size is not known.

Purpose: To determine the required training size for a desired accuracy in brain MRI segmentation in multiple sclerosis (MS) using DL.

Study Type: Retrospective analysis of MRI data acquired as part of a multicenter clinical trial.

Study Population: In all, 1008 patients with clinically definite MS.

Field Strength/sequence: MRIs were acquired at 1.5T and 3T scanners manufactured by GE, Philips, and Siemens with dual turbo spin echo, FLAIR, and T -weighted turbo spin echo sequences.

Assessment: Segmentation results using an automated analysis pipeline and validated by two neuroimaging experts served as the ground truth. A DL model, based on a fully convolutional neural network, was trained separately using 16 different training sizes. The segmentation accuracy as a function of the training size was determined. These data were fitted to the learning curve for estimating the required training size for desired accuracy.

Statistical Tests: The performance of the network was evaluated by calculating the Dice similarity coefficient (DSC), and lesion true-positive and false-positive rates.

Results: The DSC for lesions showed much stronger dependency on the sample size than gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF). When the training size was increased from 10 to 800 the DSC values varied from 0.00 to 0.86 ± 0.016 for T lesions, 0.87 ± 009 to 0.94 ± 0.004 for GM, 0.86 ± 0.08 to 0.94 ± 0.005 for WM, and 0.91 ± 0.009 to 0.96 ± 0.003 for CSF.

Data Conclusion: Excellent segmentation was achieved with a training size as small as 10 image volumes for GM, WM, and CSF. In contrast, a training size of at least 50 image volumes was necessary for adequate lesion segmentation.

Level Of Evidence: 1 Technical Efficacy Stage: 1 J. Magn. Reson. Imaging 2020;51:1487-1496.
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http://dx.doi.org/10.1002/jmri.26959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7165037PMC
May 2020

Lymphocyte counts and infection rates: Long-term fingolimod treatment in primary progressive MS.

Neurol Neuroimmunol Neuroinflamm 2019 11 11;6(6). Epub 2019 Sep 11.

From the Central Texas Neurology Consultants (E.J.F.), Round Rock, TX; Icahn School of Medicine at Mount Sinai (F.D.L.), New York, NY; McGovern Medical School (J.S.W.), The University of Texas Health Science Center at Houston (UTHealth), TX; Mellen Center for Multiple Sclerosis Treatment and Research (J.A.C.), Neurological Institute, Cleveland Clinic Foundation, OH; Oxford PharmaGenesis Ltd (I.M.W.), UK; Novartis Pharmaceuticals Corporation (X.M., M.Z., S.K.), East Hanover, NJ; and The University of California, San Francisco (UCSF); Weill Institute for Neurosciences, Department of Neurology (B.A.C.C.), San Francisco, CA.

Objective: To evaluate lymphocyte counts and incidences of infections in patients with primary progressive MS (PPMS) receiving fingolimod 0.5 mg/d or placebo over 5 years during the INFORMS study, to assess infection rates with longer-term treatment.

Methods: INFORMS was a randomized, multicenter, double-blind, placebo-controlled, parallel-group, phase 3 study of the sphingosine 1-phosphate receptor modulator fingolimod in patients with PPMS. Lymphocyte counts and incidences of infections were compared in patients receiving fingolimod or placebo. Infection rates were assessed in patients receiving fingolimod according to nadir and mean absolute lymphocyte count (ALC).

Results: Overall, 336 patients received fingolimod 0.5 mg/d (total exposure: 908.1 patient-years), and 487 received placebo (1,423.5 patient-years). In patients receiving fingolimod, mean ALC decreased by approximately 70% in the 2 weeks following treatment initiation and remained stable throughout the study. The incidences of all infections in the fingolimod and placebo groups were similar (53.6 vs 51.9 per 100 patient-years). The most common infections in patients receiving fingolimod were urinary tract infections (5.7 per 100 patient-years), upper respiratory tract infections (4.2 per 100 patient-years), and influenza (3.2 per 100 patient-years); incidences were similar in the placebo group (5.9, 4.2, and 3.1 per 100 patient-years, respectively). There was no apparent association between nadir or mean ALC and incidence of infection-related adverse events.

Conclusions: In patients with PPMS, long-term treatment with fingolimod 0.5 mg/d for up to 5 years led to an expected decrease of approximately 70% in mean ALC and did not appear to correlate with increased risk of infection.

Classification Of Evidence: Because this is a secondary analysis, this study provides Class II evidence that long-term PPMS treatment with fingolimod decreased mean ALC by approximately 70%, but did not significantly increase infection risk.
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http://dx.doi.org/10.1212/NXI.0000000000000614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745722PMC
November 2019

Chronic white matter lesion activity predicts clinical progression in primary progressive multiple sclerosis.

Brain 2019 09;142(9):2787-2799

NeuroRx Research, Montreal, QC, Canada.

Chronic active and slowly expanding lesions with smouldering inflammation are neuropathological correlates of progressive multiple sclerosis pathology. T1 hypointense volume and signal intensity on T1-weighted MRI reflect brain tissue damage that may develop within newly formed acute focal inflammatory lesions or in chronic pre-existing lesions without signs of acute inflammation. Using a recently developed method to identify slowly expanding/evolving lesions in vivo from longitudinal conventional T2- and T1-weighted brain MRI scans, we measured the relative amount of chronic lesion activity as measured by change in T1 volume and intensity within slowly expanding/evolving lesions and non-slowly expanding/evolving lesion areas of baseline pre-existing T2 lesions, and assessed the effect of ocrelizumab on this outcome in patients with primary progressive multiple sclerosis participating in the phase III, randomized, placebo-controlled, double-blind ORATORIO study (n = 732, NCT01194570). We also assessed the predictive value of T1-weighted measures of chronic lesion activity for clinical multiple sclerosis progression as reflected by a composite disability measure including the Expanded Disability Status Scale, Timed 25-Foot Walk and 9-Hole Peg Test. We observed in this clinical trial population that most of total brain non-enhancing T1 hypointense lesion volume accumulation was derived from chronic lesion activity within pre-existing T2 lesions rather than new T2 lesion formation. There was a larger decrease in mean normalized T1 signal intensity and greater relative accumulation of T1 hypointense volume in slowly expanding/evolving lesions compared with non-slowly expanding/evolving lesions. Chronic white matter lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in slowly expanding/evolving lesions and in non-slowly expanding/evolving lesion areas of pre-existing lesions predicted subsequent composite disability progression with consistent trends on all components of the composite. In contrast, whole brain volume loss and acute lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in new focal T2 lesions did not predict subsequent composite disability progression in this trial at the population level. Ocrelizumab reduced longitudinal measures of chronic lesion activity such as T1 hypointense lesion volume accumulation and mean normalized T1 signal intensity decrease both within regions of pre-existing T2 lesions identified as slowly expanding/evolving and in non-slowly expanding/evolving lesions. Using conventional brain MRI, T1-weighted intensity-based measures of chronic white matter lesion activity predict clinical progression in primary progressive multiple sclerosis and may qualify as a longitudinal in vivo neuroimaging correlate of smouldering demyelination and axonal loss in chronic active lesions due to CNS-resident inflammation and/or secondary neurodegeneration across the multiple sclerosis disease continuum.
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http://dx.doi.org/10.1093/brain/awz212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736181PMC
September 2019

Onset of clinical and MRI efficacy of ocrelizumab in relapsing multiple sclerosis.

Neurology 2019 11 4;93(19):e1778-e1786. Epub 2019 Sep 4.

From the Department of Radiology and Nuclear Medicine (F.B.), VU University Medical Centre, Amsterdam, the Netherlands; UCL Institutes of Healthcare Engineering and Neurology (F.B.), London, UK; Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering (L.K.), University Hospital Basel, University of Basel, Switzerland; Department of Neurology (J.S.W.), McGovern Medical School, UTHealth, Houston, TX; Department of Radiology (D.K.B.L.), University of British Columbia, Vancouver, Canada; Department of Neurology and Center for Neuroinflammation and Experimental Therapeutics (A.B.-O.), University of Pennsylvania, Philadelphia; Department of Neurology, Medical Faculty (H.-P.H.), Heinrich-Heine University Düsseldorf, Germany; F. Hoffmann-La Roche Ltd. (S.B., A.S., J.N., H.K.), Basel, Switzerland; Genentech, Inc. (J.H., L.J.), South San Francisco; and Department of Neurology (S.L.H.), University of California, San Francisco. During completion of the work related to this article, S. Belachew was an employee of F. Hoffmann-La Roche Ltd.; his current affiliation is Biogen, Cambridge, MA.

Objective: To assess the onset of ocrelizumab efficacy on brain MRI measures of disease activity in the phase II study in relapsing-remitting multiple sclerosis (RRMS), and relapse rate in the pooled phase III studies in relapsing multiple sclerosis (RMS).

Methods: Brain MRI activity was determined in the phase II trial at monthly intervals in patients with RRMS receiving placebo, ocrelizumab (600 mg), or intramuscular interferon (IFN) β-1a (30 μg). Annualized relapse rate (ARR; over various epochs) and time to first relapse were analyzed in the pooled population of the phase III OPERA (A Study of Ocrelizumab in Comparison With Interferon Beta-1a [Rebif] in Participants With Relapsing Multiple Sclerosis) I and OPERA II trials in patients with RMS receiving ocrelizumab (600 mg) or subcutaneous IFN-β-1a (44 μg).

Results: In patients with RRMS, ocrelizumab reduced the number of new T1 gadolinium-enhancing lesions by week 4 vs placebo ( = 0.042) and by week 8 vs intramuscular IFN-β-1a ( < 0.001). Ocrelizumab also reduced the number of new or enlarging T2 lesions appearing between weeks 4 and 8 vs both placebo and IFN-β-1a (both < 0.001). In patients with RMS, ocrelizumab significantly reduced ARR ( = 0.005) and the probability of time to first protocol-defined relapse ( = 0.014) vs subcutaneous IFN-β-1a within the first 8 weeks.

Conclusion: Epoch analysis of MRI-measured lesion activity in the phase II study and relapse rate in the phase III studies consistently revealed a rapid suppression of acute MRI and clinical disease activity following treatment initiation with ocrelizumab in patients with RRMS and RMS, respectively.

Classification Of Evidence: This study provides Class II evidence that for patients with RRMS and RMS, ocrelizumab suppressed MRI activity within 4 weeks and clinical disease activity within 8 weeks.
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http://dx.doi.org/10.1212/WNL.0000000000008189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946481PMC
November 2019

Long-term outcomes with teriflunomide in patients with clinically isolated syndrome: Results of the TOPIC extension study.

Mult Scler Relat Disord 2019 Aug 24;33:131-138. Epub 2019 May 24.

McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, United States.

Background: In the phase 3 TOPIC study, teriflunomide significantly reduced the risk of relapse determining conversion to clinically definite multiple sclerosis (CDMS) in patients with clinically isolated syndrome, versus placebo. We assessed clinical and safety outcomes associated with extended teriflunomide treatment in the TOPIC extension study.

Methods: Patients who completed the TOPIC core study (including those still on study at early termination) or converted to CDMS after at least 24 weeks in the core study were eligible to participate in the extension. The primary efficacy endpoint in the extension was time to conversion to CDMS.

Results: Risk of relapse determining conversion to CDMS was 47.1% lower in patients treated with teriflunomide 14 mg during the core and extension studies compared with patients treated with placebo during the core study and teriflunomide 14 mg during the extension. The incidence of adverse events was 75.8% and 81.9% for 7 and 14 mg teriflunomide, respectively.

Conclusions: Reduced risk of relapse determining conversion to CDMS in patients with early MS receiving teriflunomide 14 mg in the core study remained throughout the extension supporting the benefits of early treatment. No new safety signals were observed for teriflunomide 7 or 14 mg.
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http://dx.doi.org/10.1016/j.msard.2019.05.014DOI Listing
August 2019

Brain and lesion segmentation in multiple sclerosis using fully convolutional neural networks: A large-scale study.

Mult Scler 2020 09 13;26(10):1217-1226. Epub 2019 Jun 13.

Department of Diagnostic and Interventional Imaging, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.

Objective: To investigate the performance of deep learning (DL) based on fully convolutional neural network (FCNN) in segmenting brain tissues in a large cohort of multiple sclerosis (MS) patients.

Methods: We developed a FCNN model to segment brain tissues, including T2-hyperintense MS lesions. The training, validation, and testing of FCNN were based on ~1000 magnetic resonance imaging (MRI) datasets acquired on relapsing-remitting MS patients, as a part of a phase 3 randomized clinical trial. Multimodal MRI data (dual-echo, FLAIR, and T1-weighted images) served as input to the network. Expert validated segmentation was used as the target for training the FCNN. We cross-validated our results using the leave-one-center-out approach.

Results: We observed a high average (95% confidence limits) Dice similarity coefficient for all the segmented tissues: 0.95 (0.92-0.98) for white matter, 0.96 (0.93-0.98) for gray matter, 0.99 (0.98-0.99) for cerebrospinal fluid, and 0.82 (0.63-1.0) for T2 lesions. High correlations between the DL segmented tissue volumes and ground truth were observed ( > 0.92 for all tissues). The cross validation showed consistent results across the centers for all tissues.

Conclusion: The results from this large-scale study suggest that deep FCNN can automatically segment MS brain tissues, including lesions, with high accuracy.
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http://dx.doi.org/10.1177/1352458519856843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6908772PMC
September 2020

Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis.

N Engl J Med 2019 06 10;380(25):2406-2417. Epub 2019 May 10.

From Vall d'Hebron University Hospital, Barcelona (X.M.); St. Michael's Hospital, University of Toronto, Toronto (X.M.), and Montreal Neurological Institute and NeuroRx Research, Montreal (D.L.A.) - both in Canada; the Institute of Neuropathology and the Department of Neurology, University Medical Center, Göttingen, Germany (M.S.W.); the Department of Neurology, Acibadem City Clinic Tokuda Hospital, Sofia, Bulgaria (I.S.); the Department of Histology and Embryology, Poznan University of Medical Science, Poznan, Poland (K.P.-S.); the Global Clinical Development Center, EMD Serono Research and Development Institute, Billerica, MA (J.W., E.M., F.D., S.S.); and McGovern Medical School, University of Texas Health Science Center at Houston, Houston (J.S.W.).

Background: Bruton's tyrosine kinase (BTK) regulates the functions of B cells and myeloid cells that are implicated in the pathogenesis of multiple sclerosis. Evobrutinib is a selective oral BTK inhibitor that has been shown to inhibit B-cell activation both in vitro and in vivo.

Methods: In this double-blind, randomized, phase 2 trial, we assigned patients with relapsing multiple sclerosis to one of five groups: placebo, evobrutinib (at a dose of 25 mg once daily, 75 mg once daily, or 75 mg twice daily), or open-label dimethyl fumarate (DMF) as a reference. The primary end point was the total (cumulative) number of gadolinium-enhancing lesions identified on T-weighted magnetic resonance imaging at weeks 12, 16, 20, and 24. Key secondary end points included the annualized relapse rate and change from baseline in the score on the Expanded Disability Status Scale (EDSS).

Results: A total of 267 patients were randomly assigned to a trial group. The mean (±SD) total number of gadolinium-enhancing lesions during weeks 12 through 24 was 3.85±5.44 in the placebo group, 4.06±8.02 in the evobrutinib 25-mg group, 1.69±4.69 in the evobrutinib 75-mg once-daily group, 1.15±3.70 in the evobrutinib 75-mg twice-daily group, and 4.78±22.05 in the DMF group. The baseline adjusted rate ratios for the total number of lesions over time as compared with placebo were 1.45 in the evobrutinib 25-mg group (P = 0.32), 0.30 in the evobrutinib 75-mg once-daily group (P = 0.005), and 0.44 in the evobrutinib 75-mg twice-daily group (P = 0.06). The unadjusted annualized relapse rate at week 24 was 0.37 in the placebo group, 0.57 in the evobrutinib 25-mg group, 0.13 in the evobrutinib 75-mg once-daily group, 0.08 in the evobrutinib 75-mg twice-daily group, and 0.20 in the DMF group. There was no significant effect of trial group on the change from baseline in the EDSS score. Elevations in liver aminotransferase values were observed with evobrutinib.

Conclusions: Patients with relapsing multiple sclerosis who received 75 mg of evobrutinib once daily had significantly fewer enhancing lesions during weeks 12 through 24 than those who received placebo. There was no significant difference with placebo for either the 25-mg once-daily or 75-mg twice-daily dose of evobrutinib, nor in the annualized relapse rate or disability progression at any dose. Longer and larger trials are required to determine the effect and risks of evobrutinib in patients with multiple sclerosis. (Funded by EMD Serono; ClinicalTrials.gov number, NCT02975349.).
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http://dx.doi.org/10.1056/NEJMoa1901981DOI Listing
June 2019

Ocrelizumab infusion experience in patients with relapsing and primary progressive multiple sclerosis: Results from the phase 3 randomized OPERA I, OPERA II, and ORATORIO studies.

Mult Scler Relat Disord 2019 May 28;30:236-243. Epub 2019 Jan 28.

McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.

Background: Ocrelizumab is an infusible humanized monoclonal antibody that selectively depletes CD20 B cells. Infusion-related reactions (IRRs) were summarized from the OPERA I, OPERA II, and ORATORIO trials for relapsing and primary progressive multiple sclerosis (MS).

Methods: OPERA I and OPERA II were identical, randomized, double-blind, active-controlled trials that enrolled patients with relapsing MS (RMS). Patients in the ocrelizumab group initially received two 300-mg intravenous (IV) infusions separated by 14 days (on Days 1 and 15); subsequent doses were administered as single 600-mg IV infusions. Ocrelizumab-treated patients also received subcutaneous (SC) placebo injections 3 times weekly. Patients in the active comparator group received SC injections of IFN β-1a 3 times weekly, as well as placebo infusions on Days 1 and 15 and Weeks 24, 48, and 72. ORATORIO was a randomized, parallel-group, double-blind, placebo-controlled study that enrolled patients with primary progressive MS (PPMS). As in the OPERA studies, patients in the ocrelizumab group initially received two 300-mg infusions separated by 14 days; however, ORATORIO patients continued to receive this divided-dose regimen throughout the study. The ORATORIO control group received IV placebo. Prior to each infusion, all patients in the OPERA and ORATORIO studies were pretreated with 100 mg IV methylprednisolone; additional prophylactic treatment with analgesics, antipyretics, and/or an IV or oral antihistamine was optional. IRRs were defined as adverse events that occurred during or within 24 h of IV infusion of ocrelizumab or placebo.

Results: Safety analyses included 1651 patients with RMS from OPERA I and OPERA II (ocrelizumab, n = 825; IFN β-1a, n = 826) and 725 patients with PPMS from ORATORIO (ocrelizumab, n = 486; placebo, n = 239). Across studies, IRRs were reported in 34.3% (vs 9.7% with IFN β-1a) and 39.9% (vs 25.5% with placebo) of ocrelizumab-treated patients in the pooled OPERA and ORATORIO populations, respectively. The majority of IRRs were mild to moderate in the OPERA (ocrelizumab, 92.6%; IFN β-1a, 98.8%) and ORATORIO (ocrelizumab, 96.9%; placebo, 93.4%) studies. IRRs most commonly occurred with the first infusion. Severe IRRs were reported in 2.4% of ocrelizumab-treated patients in the OPERA studies (vs 0.1% with IFN β-1a) and 1.2% of ocrelizumab-treated patients in ORATORIO (vs 1.7% with placebo). Two serious IRRs occurred across the OPERA studies, both of which occurred with the initial infusion. The first event occurred in an IFN β-1a-treated patient in association with the initial infusion of IV placebo and consisted of severe balance disorder, dizziness, flushing, and hypoesthesia. The second event was a life-threatening reaction (bronchospasm) that occurred in an ocrelizumab-treated patient 15 min after the infusion started. Frequently reported IRR symptoms included pruritus, rash, throat irritation, and flushing. Premedication use, particularly antihistamines, was associated with fewer IRRs.

Conclusion: Findings from the OPERA I, OPERA II, and ORATORIO trials show that IRRs were the most frequently reported adverse events with ocrelizumab, were mostly mild to moderate in severity, were reduced with appropriate pretreatment, and decreased with subsequent dosing. IRRs that did occur were effectively managed through infusion rate adjustment and symptomatic treatment.
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http://dx.doi.org/10.1016/j.msard.2019.01.044DOI Listing
May 2019

Ocrelizumab efficacy in subgroups of patients with relapsing multiple sclerosis.

J Neurol 2019 May 28;266(5):1182-1193. Epub 2019 Feb 28.

Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.

Objective: The efficacy and safety of ocrelizumab, versus interferon (IFN) β-1a, for the treatment of relapsing multiple sclerosis (RMS) from the identically designed OPERA I (NCT01247324) and OPERA II (NCT01412333) phase III studies has been reported; here we present subgroup analyses of efficacy endpoints from the pooled OPERA I and OPERA II populations.

Methods: Patients with RMS were randomized to either ocrelizumab 600 mg administered by intravenous infusion every 24 weeks or subcutaneous IFN β-1a 44 µg three times per week throughout the 96-week treatment period. Relapse, disability, and MRI outcomes were analyzed for predefined and post hoc subgroups based on demographic and disease characteristics along with prior treatment using appropriate statistical tests to determine the treatment effect in subgroups and treatment-by-subgroup interactions.

Results: The significant treatment benefit of ocrelizumab, versus IFN β-1a, observed in the overall OPERA I and OPERA II pooled populations was maintained across most subgroup strata for all endpoints, including annualized relapse rate, disability progression, and MRI outputs.

Conclusions: The treatment effect of ocrelizumab versus IFN β-1a, measured by clinical and MRI outcomes, was maintained across most of the subgroups and strata of interest, and the pattern of treatment benefit across all subgroups was consistent with that from the pooled OPERA studies.
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http://dx.doi.org/10.1007/s00415-019-09248-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469695PMC
May 2019

Slowly expanding/evolving lesions as a magnetic resonance imaging marker of chronic active multiple sclerosis lesions.

Mult Scler 2019 12 19;25(14):1915-1925. Epub 2018 Dec 19.

NeuroRx Research, Montreal, QC, Canada/Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.

Background: Chronic lesion activity driven by smoldering inflammation is a pathological hallmark of progressive forms of multiple sclerosis (MS).

Objective: To develop a method for automatic detection of slowly expanding/evolving lesions (SELs) on conventional brain magnetic resonance imaging (MRI) and characterize such SELs in primary progressive MS (PPMS) and relapsing MS (RMS) populations.

Methods: We defined SELs as contiguous regions of existing T2 lesions showing local expansion assessed by the Jacobian determinant of the deformation between reference and follow-up scans. SEL candidates were assigned a heuristic score based on concentricity and constancy of change in T2- and T1-weighted MRIs. SELs were examined in 1334 RMS patients and 555 PPMS patients.

Results: Compared with RMS patients, PPMS patients had higher numbers of SELs ( = 0.002) and higher T2 volumes of SELs ( < 0.001). SELs were devoid of gadolinium enhancement. Compared with areas of T2 lesions not classified as SEL, SELs had significantly lower T1 intensity at baseline and larger decrease in T1 intensity over time.

Conclusion: We suggest that SELs reflect chronic tissue loss in the absence of ongoing acute inflammation. SELs may represent a conventional brain MRI correlate of chronic active MS lesions and a candidate biomarker for smoldering inflammation in MS.
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http://dx.doi.org/10.1177/1352458518814117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876256PMC
December 2019

Exploring the relationship between Endothelin-1 and peripheral inflammation in multiple sclerosis.

J Neuroimmunol 2019 01 15;326:45-48. Epub 2018 Nov 15.

Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.

Background: Identifying pathways linking neuroinflammation and neurodegeneration is essential to help prevent disability progression in people with multiple sclerosis (MS). Endothelin-1 (ET-1) is a potent vasoconstrictor thought to contribute to cerebral hypoperfusion and tissue damage in MS. Its link with the neuroinflammatory process remains poorly investigated.

Objectives: To determine plasma ET-1 levels in treatment-naïve people with MS and controls, and the relationship between ET-1 and other peripheral immune mediator levels as potential markers of the disease process.

Methods: This is a retrospective study that included specimens previously collected from 35 treatment-naïve patients with clinically isolated syndrome highly suggestive of MS or definite MS and 35 sex- and age-matched controls. ET-1 plasma levels were measured by enzyme-linked immunosorbent assay (ELISA), and plasma cytokine levels [interleukin (IL)-1beta, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12(p70), IL-13, interferon (IFN)-γ and tumor necrosis factor (TNF)-α] were simultaneously measured by Multiplex assay.

Results: ET-1 levels were significantly increased in MS patients compared to controls. No significant difference in cytokine levels between the groups were found. However, a significant increase in IFN-γ/IL-4 ratio was observed in patients with MS in comparison with controls, suggestive of Th1 skewed response. Binary logistic regression was performed to ascertain the effects of age, sex, ET-1 and cytokine levels on the likelihood of MS diagnosis. In the final model, ET-1, IL-4 and IFN-γ levels remained as predictors of MS. There was no significant correlation between ET-1 and cytokine levels.

Conclusions: Patients with MS presented increased levels of ET-1 and an immune response biased towards a Th1 profile. Although both ET-1 and Th1 cytokine profile were predictors of MS diagnosis, ET-1 levels were not associated with peripheral immune markers, suggesting that these changes may occur independently.
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http://dx.doi.org/10.1016/j.jneuroim.2018.11.007DOI Listing
January 2019

Ocrelizumab reduces progression of upper extremity impairment in patients with primary progressive multiple sclerosis: Findings from the phase III randomized ORATORIO trial.

Mult Scler 2018 12 12;24(14):1862-1870. Epub 2018 Nov 12.

Department of Neurology, Queen Mary University of London, London, UK.

Background: Upper extremity (UE) impairment is common with primary progressive multiple sclerosis (PPMS).

Objective: This exploratory analysis examined the effects of ocrelizumab on confirmed progression (CP) and confirmed improvement (CI) in UE impairment in patients from ORATORIO.

Methods: Patients with PPMS received ocrelizumab 600 mg or placebo every 24 weeks for ⩾120 weeks. The Nine-Hole Peg Test (9HPT) was administered at baseline (BL) and every 12 weeks thereafter. Prespecified exploratory endpoints included change in 9HPT time and proportion of patients with CP of ⩾20% in 9HPT. Analysis populations included intention-to-treat (ITT) patients and subgroups stratified by BL 9HPT time and Expanded Disability Status Scale. Post hoc analyses included the proportion of patients achieving more severe thresholds of CP and the proportion achieving CI in 9HPT.

Results: Among ITT patients, ocrelizumab significantly reduced the change in 9HPT time over 120 weeks, the risk of CP of ⩾20% in 9HPT time for both hands and the risk of more severe 9HPT progression versus placebo. Numerical trends also favoured ocrelizumab versus placebo with respect to achieving CI. Consistent directional trends were observed in subgroup analyses.

Conclusion: Ocrelizumab reduces the risk of UE disability progression and may increase the possibility of improvement versus placebo in PPMS.
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http://dx.doi.org/10.1177/1352458518808189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282157PMC
December 2018

Trial of Fingolimod versus Interferon Beta-1a in Pediatric Multiple Sclerosis.

N Engl J Med 2018 09;379(11):1017-1027

From the Partners Pediatric Multiple Sclerosis Center, Massachusetts General Hospital, Boston (T.C.); Montreal Neurological Institute, McGill University, and NeuroRx Research - both in Montreal (D.L.A.); Children's Hospital of Philadelphia (B.B.) and the Center for Neuroinflammation and Experimental Neurotherapeutics and the Department of Neurology (A.B.-O.), Perelman School of Medicine, University of Pennsylvania - all in Philadelphia; the Department of Neuropathology (W.B.) and the Department of Pediatrics and Adolescent Medicine, German Center for Multiple Sclerosis in Childhood and Adolescence (J.G.), University Medical Center Göttingen, Göttingen, and the Division of Pediatric Neurology, Children's Hospital Datteln, Witten/Herdecke University, Datteln (K.R.) - all in Germany; Gallarate Hospital, Gallarate, Italy (A.G.); Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London (G.G.); the University of Texas Southwestern Medical Center, Children's Health, Dallas (B.G.), and McGovern Medical School, University of Texas Health Science Center at Houston, Houston (J.S.W.) - both in Texas; Pediatric Multiple Sclerosis Center at NYU Langone, New York (L.K.); Hôpitaux Universitaires Paris-Sud, Assistance Publique-Hôpitaux de Paris, Paris (M.T.); the Department of Neurology, University of California at San Francisco, San Francisco (E.W.); Novartis Pharmaceuticals, East Hanover, NJ (T.S., Y.C., N.P.); and Novartis Pharma, Basel, Switzerland (M.M.).

Background: Treatment of patients younger than 18 years of age with multiple sclerosis has not been adequately examined in randomized trials. We compared fingolimod with interferon beta-1a in this population.

Methods: In this phase 3 trial, we randomly assigned patients 10 to 17 years of age with relapsing multiple sclerosis in a 1:1 ratio to receive oral fingolimod at a dose of 0.5 mg per day (0.25 mg per day for patients with a body weight of ≤40 kg) or intramuscular interferon beta-1a at a dose of 30 μg per week for up to 2 years. The primary end point was the annualized relapse rate.

Results: Of a total of 215 patients, 107 were assigned to fingolimod and 108 to interferon beta-1a. The mean age of the patients was 15.3 years. Among all patients, there was a mean of 2.4 relapses during the preceding 2 years. The adjusted annualized relapse rate was 0.12 with fingolimod and 0.67 with interferon beta-1a (absolute difference, 0.55 relapses; relative difference, 82%; P<0.001). The key secondary end point of the annualized rate of new or newly enlarged lesions on T-weighted magnetic resonance imaging (MRI) was 4.39 with fingolimod and 9.27 with interferon beta-1a (absolute difference, 4.88 lesions; relative difference, 53%; P<0.001). Adverse events, excluding relapses of multiple sclerosis, occurred in 88.8% of patients who received fingolimod and 95.3% of those who received interferon beta-1a. Serious adverse events occurred in 18 patients (16.8%) in the fingolimod group and included seizures (in 4 patients), infection (in 4 patients), and leukopenia (in 2 patients). Serious adverse events occurred in 7 patients (6.5%) in the interferon beta-1a group and included infection (in 2 patients) and supraventricular tachycardia (in 1 patient).

Conclusions: Among pediatric patients with relapsing multiple sclerosis, fingolimod was associated with a lower rate of relapse and less accumulation of lesions on MRI over a 2-year period than interferon beta-1a but was associated with a higher rate of serious adverse events. Longer studies are required to determine the durability and safety of fingolimod in pediatric multiple sclerosis. (Funded by Novartis Pharma; PARADIGMS ClinicalTrials.gov number, NCT01892722 .).
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http://dx.doi.org/10.1056/NEJMoa1800149DOI Listing
September 2018