Background: Predicting treatment response and disease progression in multiple sclerosis (MS) is challenging. Treatment Response Scoring Systems (TRSS) are potentially useful, but their utility in patients receiving high-efficacy therapies and very high-efficacy therapies (HET/vHET) remains unclear. Objective: This study aimed to evaluate the performance of TRSS in patients treated with HET/vHET. Methods: We retrospectively studied MS patients treated with HET/vHET in an MS specialized centre. TRSS, including the Rio Score, modified Rio Score and MAGNIMS score, were applied to assess response to treatment. We evaluated the predictive value of the TRSS on disease activity and disability progression. Results: TRSS effectively predicted disease activity and progression of disability in patients treated with HET/vHET. Patients with high TRSS scores at 12 months post-HET/vHET initiation had a significantly increased risk of relapses, new lesions on magnetic resonance imaging (MRI) scans and progression of disability at 4 years. Discussion: Our findings highlight the importance of personalized treatment strategies in MS. TRSS are valuable tools for monitoring treatment response, guiding clinical decision-making and optimizing patient care.
Objectives: To investigate, during the 5-year period without treatment after termination of a 2-year clinical trial of interferon beta-1b for the treatment of primary progressive multiple sclerosis, differences in the evolution of clinical variables and magnetic resonance imaging results between trial arms and to investigate correlations between in-trial changes in Multiple Sclerosis Functional Composite (MSFC) score and magnetic resonance imaging variables and Expanded Disability Status Scale (EDSS) score evolution.Design: Five-year clinical trial follow-up.
Abstract Objective Grey matter (GM) atrophy occurs in all multiple sclerosis (MS) phenotypes. We investigated whether there is a spatiotemporal pattern of GM atrophy that is associated with faster disability accumulation in MS. Methods We analysed 3,604 brain high-resolution T1-weighted MRI scans from 1,417 participants: 1,214 MS patients (253 clinically-isolated syndrome[CIS], 708 relapsingremitting[RRMS], 128 secondary-progressive[SPMS], 125 primary-progressive[PPMS]), over an average follow-up of 2.41 years (standard deviation[SD]=1.97), and 203 healthy controls (HCs) [average follow-up=1.83 year, SD=1.77], attending 7 European centres. Disability was assessed with the Expanded-Disability Status Scale (EDSS). We obtained volumes of the deep GM (DGM), temporal, frontal, parietal, occipital and cerebellar GM, brainstem and cerebral white matter. Hierarchical mixed-models assessed annual percentage rate of regional tissue loss and identified regional volumes associated with time-to-EDSS progression. Results SPMS showed the lowest baseline volumes of cortical GM and DGM. Of all baseline regional volumes, only that of the DGM predicted time-to-EDSS progression (hazard ratio=0.73, 95% CIs 0.65, 0.82; p <0.001): for every standard deviation decrease in baseline DGM volume, the risk of presenting a shorter time to EDSS worsening during follow-up increased by 27%. Of all longitudinal measures, DGM showed the fastest annual rate of atrophy, which was faster in SPMS (-1.45%), PPMS (-1.66%), and RRMS (-1.34%) than CIS (-0.88%) and HCs (-0.94%)[ p <0.01]. The rate of temporal GM atrophy in SPMS (-1.21%) was significantly faster than RRMS (-0.76%), CIS (-0.75%), and HCs (-0.51%). Similarly, the rate of parietal GM atrophy in SPMS (-1.24-%) was faster than CIS (-0.63%) and HCs (-0.23%) (all p values <0.05). Only the atrophy rate in DGM in patients was significantly associated with disability accumulation (beta=0.04, p <0.001). Interpretation This large multi-centre and longitudinal study shows that DGM volume loss drives disability accumulation in MS, and that temporal cortical GM shows accelerated atrophy in SPMS than RRMS. The difference in regional GM atrophy development between phenotypes needs to be taken into account when evaluating treatment effect of therapeutic interventions.
Structural network-based approaches can assess white matter connections revealing topological alterations in multiple sclerosis (MS). However, principal network (PN) organisation and its clinical relevance in MS has not been explored yet. Here, structural networks were reconstructed from diffusion data in 58 relapsing-remitting MS (RRMS), 28 primary progressive MS (PPMS), 36 secondary progressive (SPMS) and 51 healthy controls (HCs). Network hubs' strengths were compared with HCs. Then, PN analysis was performed in each clinical subtype. Regression analysis was applied to investigate the associations between nodal strength derived from the first and second PNs (PN1 and PN2) in MS, with clinical disability. Compared with HCs, MS patients had preserved hub number, but some hubs exhibited reduced strength. PN1 comprised 10 hubs in HCs, RRMS and PPMS but did not include the right thalamus in SPMS. PN2 comprised 10 hub regions with intra-hemispheric connections in HCs. In MS, this subnetwork did not include the right putamen whilst in SPMS the right thalamus was also not included. Decreased nodal strength of the right thalamus and putamen from the PNs correlated strongly with higher clinical disability. These PN analyses suggest distinct patterns of disruptions in MS subtypes which are clinically relevant.
Background: Clinical studies in multiple sclerosis (MS) often require accurate measurement of walking distance. Utilisation of electronic devices could theoretically improve this. Mobile devices have the potential to continuously monitor health by collecting movement data. Popular fitness trackers record steps taken and distance travelled, typically using a fixed-stride length. However, applications using fixed-stride length may be less accurate in those with altered gait patterns. While useful for everyday purposes, medical monitoring requires greater accuracy. Objective: Our aim was to determine the agreement and reliability of using a smartphone application to measure distance walked. Method: A phone application (mSteps) was developed and tested in a pilot study and then a validation study, looking at an indoor and outdoor setting with people with multiple sclerosis (PwMS) and a control cohort. Results: In the pilot study, the 95% limits of agreement (LOA) for outdoor tracking in control cohort lay within the a priori defined limit; however, the indoor tracking in both cohorts did not meet the defined limit. The app was then successfully validated outdoors in PwMS. Conclusion: mSteps could be used to accurately measure distance outdoors in PwMS. There is still a need for solutions to accurately and reliably measure distance walked indoors.
Organizing pneumonia (OP), an interstitial lung disease, has been observed in patients with inflammatory demyelinating diseases (IDDs) treated with anti-CD20, particularly after COVID-19, but data are limited.
The diagnostic criteria used in primary progressive (PP) and relapsing—remitting (RR) multiple sclerosis (MS) show substantial differences. This introduces complexity in the diagnosis of MS which could be resolved if these criteria could be unified in terms of the requirements for dissemination in space (DIS). The aim of this study was to assess whether a single algorithm may be used to demonstrate DIS in all forms of MS. Five sets of RRMS criteria for DIS were applied to a cohort of 145 patients with established PPMS (mean disease duration: 11 years — PPMS-1): C1: Barkhof—Tintoré (as in 2005 McDonald’s criteria); C2: Swanton et al. (as in JNNP 2006); C3: presence of oligoclonal bands plus two lesions (as in McDonald’s criteria); C4 and C5: a two-step approach was also followed (patients not fulfilling C1 or C2 were then assessed for C3). Two sets of PPMS criteria for DIS were applied: C6: Thompson et al. (as in 2001 McDonald’s criteria); C7: 2005 McDonald criteria. A second sample of 55 patients with less than 5 years of disease duration (PPMS-2) was also analysed using an identical approach. For PPMS-1/PPMS-2, fulfilment was: C1:73.8%/66.7%; C2:72.1%/59.3%; C3:89%/79.2%; C4:96%/92.3%; C5:96%/85.7%; C6:85.8%/78.7%; C7:91%/80.4%. Levels of fulfilment suggest that the use of a single set of criteria for DIS in RRMS and PPMS might be feasible, and reinforce the added value of cerebrospinal fluid (CSF) findings to increase fulfilment in PPMS. Unification of the DIS criteria for both RRMS and PPMS could be considered in further revisions of the MS diagnostic criteria.
Objective: To assess ocrelizumab efficacy on upper limb function in more disabled/older patients with primary progressive multiple sclerosis (PPMS) from the Phase III ORATORIO study (NCT01194570) to inform the design of the Phase IIIb ORATORIO-HAND study. Background: Ocrelizumab demonstrated efficacy versus placebo in reducing upper limb dysfunction (9-Hole Peg Test [9HPT]) in ORATORIO (Expanded Disability Status Scale [EDSS] ≤6.5). Ocrelizumab benefit in more disabled PPMS patients ineligible for inclusion in ORATORIO would fulfill an unmet need. Design/Methods: ORATORIO PPMS patients (N=732; EDSS 3.0–6.5; age 18–55 years) were randomized (2:1) to ocrelizumab or placebo for ≥120 weeks and until a pre-specified number of EDSS progression events occurred. Efficacy of ocrelizumab in preventing progression of upper limb function as measured by 12-week confirmed 20% worsening in 9HPT (average of both hands) was investigated in baseline subgroups: EDSS ≥6.0 (N=220), age >45 years (N=384), and 9HPT time >25 seconds (N=434). Results: Ocrelizumab reduced upper limb disability progression in more disabled/older PPMS patients. Risk reductions versus placebo in 9HPT progression were similar in patients with baseline EDSS score 25s (49% versus 44%, p=0.82). Progression events mainly occurred in patients with 9HPT >25s versus ≤25s (placebo: 34.3% vs 17.8%; ocrelizumab: 21.5% vs 9.9%); a weak trend for greater efficacy in patients ≤45 years versus >45 years was observed (p=0.29). Conclusions: ORATORIO-HAND is designed to further investigate the efficacy of ocrelizumab on upper limb function. Based on the 9HPT progression rates observed in ORATORIO, 1000 eligible patients (EDSS 3.0─8.0, age 18–65 years, 9HPT >25s), randomized (1:1) to ocrelizumab or placebo for ≥120 weeks (until a pre-specified number of progression events occur) will enable the assessment of ocrelizumab efficacy on confirmed 9HPT progression (primary endpoint). Screening will begin Q1 2019. Disclosure: Dr. Giovannoni has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AbbVie, Biogen, Novartis, Teva Neuroscience and Roche Diagnostics Corporation. He has also received consultancy fees for advisory board meetings for Merck-Serono, Genzyme-Sanofi, Synthon BV, and Physicians’ Summit and several medical education meetings. Dr. Giovannoni has received personal compensation in an editorial capacity for Multiple Sclerosis and Related Disorders (Elsevier). Dr. Giovannoni has received research support from Takeda Pharmaceutical Company. Dr. Airas has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche, Merck . Dr. Airas has received research support from Sanofi-Genzyme. Dr. Bove has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Roche Genentech and Genzyme Sanofi. Dr. Bove has received research support from Akili Interactive. Dr. Boyko has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Schering, Merck, TEVA, Novartis, Sanofi-Genzyme, Actelion, Biocad, Generium. Dr. Cutter has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AMO Pharmaceuticals, Biolinerx, Horizon Pharmaceuticals, Hisun Pharmaceuticals, Merck, Merck/Pfizer, Opko Biologics, Neurim, Novartis, Ophazyme, Sanofi-Aventis, Reata Pharmaceuticals, Receptos/Celgene, Teva pharmaceuticals, NHLBI, NICHD, Atara Biotherapeutics, Axon, Biogen, Argenix, Brainstorm Cell Therapeutics, Charleston Labs Inc, Click Therapeutics, Genzyme, Genentech, GW Pharma, Klein-Buendel Incorporated, Medimmune, Medday, Novartis, Roche, Scifluor, Somahlution, Teva pharmaceuticals, TG Therapeutics, UT Houston. Dr. Cutter has received personal compensation in an editorial capacity for Statistical editor for the Journal of the American Society of Nephrology. Dr. Cutter has received research support from Via MGFA. Dr. Hobart has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acorda, Asubio, Bayer Schering, Biogen Idec, F. Hoffmann-La Roche Ltd, Genzyme, Merck Serono, Novartis, Oxford PharmaGenesis, Oxford Health Policy Forum and Teva. Dr. Kuhle’s institution has received compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Novartis Pharmaceuticals, Protagen AG, Roche, Teva, Sanofi Genzyme, Swiss MS Society, and Merck Serono,. Dr. Kuhle has received research support from ECTRIMS Research Fellowship Programme, Bayer AG, Biogen, Sanofi Genzyme, Merck, Novartis Pharmaceuticals, Roche, Swiss MS Society, Swiss National Research Foundation, and University of Basel. Dr. Oh has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with EMD-Serono, Novartis, Biogen-Idec, Sanofi-Genzyme, Roche, Celgene. Dr. Oh has received research support from Biogen-Idec, Sanofi-Genzyme. Dr. Tur has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Bayer, F. Hoffmann-La Roche Ltd, Ismar Healthcare, Merck Serono, Novartis, Sanofi and Teva. Dr. Tur has received research support from Postdoctoral research ECTRIMS Fellowships. Dr. Garas has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche Ltd. Dr. Model has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche Ltd. Dr. Manfrini has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with F. Hoffmann-La Roche Ltd as an employee. Dr. Wolinsky has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alkermes, Actelion, Acorda Therapeutics, Celgene, EMD Serono, GeNeuro, GW Pharma, MedDay Pharmaceuticals, Novartis, Otsuka, PTC Therapeutics, Roche/Genentech, Sanofi Genzyme, PlatformQ Health Education, PRIME, and Strategic Consultants Intl. Dr. Wolinsky has received royalty, license fees, or contractual rights payments from UTHealth to Millipore (Chemicon International) Corporation.
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