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Supplemental material, sj-docx-1-msj-10.1177_13524585231151951 for Early non-disabling relapses are important predictors of disability accumulation in people with relapsing-remitting multiple sclerosis by Cyrus Daruwalla, Vahid Shaygannejad, Serkan Ozakbas, Eva Kubala Havrdova, Dana Horakova, Raed Alroughani, Cavit Boz, Francesco Patti, Marco Onofrj, Alessandra Lugaresi, Sara Eichau, Marc Girard, Alexandre Prat, Pierre Duquette, Bassem Yamout, Samia J Khoury, Seyed Aidin Sajedi, Recai Turkoglu, Ayse Altintas, Olga Skibina, Katherine Buzzard, Pierre Grammond, Rana Karabudak, Anneke van der Walt, Helmut Butzkueven, Davide Maimone, Jeannette Lechner-Scott, Aysun Soysal, Nevin John, Julie Prevost, Daniele Spitaleri, Cristina Ramo-Tello, Oliver Gerlach, Gerardo Iuliano, Matteo Foschi, Radek Ampapa, Vincent van Pesch, Michael Barnett, Nevin Shalaby, Marie D’hooghe, Jens Kuhle, Maria Jose Sa, Marzena Fabis-Pedrini, Allan Kermode, Saloua Mrabet, Riadh Gouider, Suzanne Hodgkinson, Guy Laureys, Liesbeth Van Hijfte, Richard Macdonell, Celia Oreja-Guevara, Edgardo Cristiano, Pamela McCombe, Jose Luis Sanchez-Menoyo, Bhim Singhal, Yolanda Blanco, Stella Hughes, Justin Garber, Claudio Solaro, Chris McGuigan, Bruce Taylor, Koen de Gans, Mario Habek, Abdullah Al-Asmi, Simu Mihaela, Tamara Castillo Triviño, Talal Al-Harbi, Juan Ignacio Rojas, Orla Gray, Dheeraj Khurana, Bart Van Wijmeersch, Nikolaos Grigoriadis, Jihad Inshasi, Jiwon Oh, Eduardo Aguera-Morales, Yara Fragoso, Fraser Moore, Cameron Shaw, Seyed Mohammad Baghbanian, Neil Shuey, Barbara Willekens, Todd A Hardy, Danny Decoo, Angel Perez sempere, Deborah Field, Ray Wynford-Thomas, Nick G Cunniffe, Izanne Roos, Charles B Malpas, Alasdair J Coles, Tomas Kalincik and J William L Brown in Multiple Sclerosis Journal

Guillain Barré syndrome (GBS) and its variants, and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP and its variants, are regarded as immune mediated neuropathies. Unlike in many autoimmune disorders, GBS and CIDP are more common in males than females. Sex is not a clear predictor of outcome. Experimental autoimmune neuritis (EAN) is an animal model of these diseases, but there are no studies of the effects of sex in EAN. The pathogenesis of GBS and CIDP involves immune response to non-protein antigens, antigen presentation through non-conventional T cells and, in CIDP with nodopathy, IgG4 antibody responses to antigens. There are some reported sex differences in some of these elements of the immune system and we speculate that these sex differences could contribute to the male predominance of these diseases, and suggest that sex differences in peripheral nerves is a topic worthy of further study.

Here we report on two unrelated adult patients presenting with Limb girdle muscular dystrophy who were found to have novel variants in ANO5. Both patients had prominent weakness of their proximal lower limbs with mild weakness of elbow flexion and markedly elevated creatine kinase. Next generation sequencing using a custom-designed neuromuscular panel was performed in both patients. In one patient, 336 genes were targeted for casual variants and in the other patient (using a later panel design), 464 genes were targeted. One patient was homozygous for a novel splice variant [c.294+5G>A; p.(Ala98Ins4*)] in ANO5. Another patient was compound heterozygous for two variants in ANO5; a common frameshift variant [c.191dupA; p.(Asn64fs)] and a novel missense variant [c.952G>C; p.(Ala318Pro)]. These findings support the utility of next generation sequencing in the diagnosis of patients presenting with a Limb girdle muscular dystrophy phenotype and extends the genotypic spectrum of ANO5 disease.

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

Additional file 2: Supplementary Methods and Figures. Fig. S1. Functional Annotation and Mapping (FUMA) histogram summary. Fig. S2. Functional Annotation and Mapping (FUMA) gene expression heat map. Fig. S3. S-LDSC annotation enrichment in ALS GWAS. Fig. S4. S-LDSC finds CNS and musculoskeletal cell-type categories are enriched in ALS GWAS. Fig. S5. Summary statistics-based Mendelian Randomisation (SMR) analysis identifies GPX3 and TNIP1. Fig. S6. TWAS-CONTENT full model GPX3 and TNIP1 gene expression variance. Fig. S7. Gene correlation across tissues. Fig. S8. Microarray expression data of TNIP1 and GPX3 demonstrate no difference in expression between cases and controls or genotype. Fig. S9. Preliminary Discovery cohort data demonstrated association with GPX3 and ALS. Fig. S10. Replication GPX3 cohort. Fig. S11. Preliminary longitudinal data assessment of ALSFRS-R and GPX3 levels. Fig. S12. TNIP1 and GPX3 methylation in ALS and control blood. Fig. S13. Knockdown of GPX3 and TNIP1 in human motor neurons. Fig. S14. Motor and developmental effect of GPX3 overexpression in zebrafish. Fig. S15. Effect-size sensitivity analysis. Fig. S16. GPX and GPX3 expression pattern across tissues. Fig. S17. Gpx3 amplicon for danio rerio. Fig. S18. pME-dre_gpx3_Codon_optimised plasmid.

Additional file 1 Contains Online Resource 1 - Supplementary Methods, and Online Resource 2 - Supplementary Tables (S1 to S4) and Supplementary Figrues (S1 to S7).

Supplemental material, sj-pdf-1-msj-10.1177_1352458520981300 for Determinants of therapeutic lag in multiple sclerosis by Izanne Roos, Emmanuelle Leray, Federico Frascoli, Romain Casey, J William L Brown, Dana Horakova, Eva Kubala Havrdova, Marc Debouverie, Maria Trojano, Francesco Patti, Guillermo Izquierdo, Sara Eichau, Gilles Edan, Alexandre Prat, Marc Girard, Pierre Duquette, Marco Onofrj, Alessandra Lugaresi, Pierre Grammond, Jonathan Ciron, Aurélie Ruet, Serkan Ozakbas, Jérôme De Seze, Céline Louapre, Hélène Zephir, Maria José Sá, Patrizia Sola, Diana Ferraro, Pierre Labauge, Gilles Defer, Roberto Bergamaschi, Christine Lebrun-Frenay, Cavit Boz, Elisabetta Cartechini, Thibault Moreau, David Laplaud, Jeannette Lechner-Scott, Francois Grand’Maison, Oliver Gerlach, Murat Terzi, Franco Granella, Raed Alroughani, Gerardo Iuliano, Vincent Van Pesch, Bart Van Wijmeersch, Daniele LA Spitaleri, Aysun Soysal, Eric Berger, Julie Prevost, Eduardo Aguera-Morales, Pamela McCombe, Tamara Castillo Triviño, Pierre Clavelou, Jean Pelletier, Recai Turkoglu, Bruno Stankoff, Olivier Gout, Eric Thouvenot, Olivier Heinzlef, Youssef Sidhom, Riadh Gouider, Tunde Csepany, Bertrand Bourre, Abdullatif Al Khedr, Olivier Casez, Philippe Cabre, Alexis Montcuquet, Abir Wahab, Jean-Philippe Camdessanche, Aude Maurousset, Ivania Patry, Karolina Hankiewicz, Corinne Pottier, Nicolas Maubeuge, Céline Labeyrie, Chantal Nifle, Alasdair Coles, Charles B Malpas, Sandra Vukusic, Helmut Butzkueven and Tomas Kalincik in Multiple Sclerosis Journal

Gut microbiota studies have been well-investigated for neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, however, fewer studies have comprehensively examined the gut microbiome in Motor Neuron Disease (MND), with none examining its impact on disease prognosis. Here, we investigate MND prognosis and the fecal microbiota, using 16S rRNA case–control data from 100 individuals with extensive medical histories and metabolic measurements. We contrast the composition and diversity of fecal microbiome signatures from 49 MND and 51 healthy controls by combining current gold-standard 16S microbiome pipelines. Using stringent quality control thresholds, we conducted qualitative assessment approaches including; direct comparison of taxa, PICRUSt2 predicted metagenomics, Shannon and Chao1-index and Firmicutes/Bacteroidetes ratio. We show that the fecal microbiome of patients with MND is not significantly different from that of healthy controls that were matched by age, sex, and BMI, however there are distinct differences in Beta-diversity in some patients with MND. Weight, BMI, and metabolic and clinical features of disease in patients with MND were not related to the composition of their fecal microbiome, however, we observe a greater risk for earlier death in patients with MND with increased richness and diversity of the microbiome, and in those with greater Firmicutes to Bacteroidetes ratio. This was independent of anthropometric, metabolic, or clinical features of disease, and warrants support for further gut microbiota studies in MND. Given the disease heterogeneity in MND, and complexity of the gut microbiota, large studies are necessary to determine the detailed role of the gut microbiota and MND prognosis.

Supplemental material, MSJ926955_supplementary_material for Disability outcomes of early cerebellar and brainstem symptoms in multiple sclerosis by Minh Le, Charles Malpas, Sifat Sharmin, Dana Horáková, Eva Havrdova, Maria Trojano, Guillermo Izquierdo, Sara Eichau, Serkan Ozakbas, Alessandra Lugaresi, Alexandre Prat, Marc Girard, Pierre Duquette, Catherine Larochelle, Raed Alroughani, Roberto Bergamaschi, Patrizia Sola, Diana Ferraro, Pierre Grammond, Francois Grand’ Maison, Murat Terzi, Cavit Boz, Raymond Hupperts, Helmut Butzkueven, Eugenio Pucci, Franco Granella, Vincent Van Pesch, Aysun Soysal, Bassem I. Yamout, Jeannette Lechner-Scott, Daniele LA Spitaleri, Radek Ampapa, Recai Turkoglu, Gerardo Iuliano, Cristina Ramo-Tello, Jose Luis Sanchez-Menoyo, Youssef Sidhom, Riadh Gouider, Vahid Shaygannejad, Julie Prevost, Ayse Altintas, Yara Dadalti Fragoso, Pamela Ann McCombe, Thor Petersen, Mark Slee, Michael H Barnett, Steve Vucic, Anneke Van Der Walt and Tomas Kalincik in Multiple Sclerosis Journal

Supplemental material, MSJ926955_appendix_1 for Disability outcomes of early cerebellar and brainstem symptoms in multiple sclerosis by Minh Le, Charles Malpas, Sifat Sharmin, Dana Horáková, Eva Havrdova, Maria Trojano, Guillermo Izquierdo, Sara Eichau, Serkan Ozakbas, Alessandra Lugaresi, Alexandre Prat, Marc Girard, Pierre Duquette, Catherine Larochelle, Raed Alroughani, Roberto Bergamaschi, Patrizia Sola, Diana Ferraro, Pierre Grammond, Francois Grand’ Maison, Murat Terzi, Cavit Boz, Raymond Hupperts, Helmut Butzkueven, Eugenio Pucci, Franco Granella, Vincent Van Pesch, Aysun Soysal, Bassem I. Yamout, Jeannette Lechner-Scott, Daniele LA Spitaleri, Radek Ampapa, Recai Turkoglu, Gerardo Iuliano, Cristina Ramo-Tello, Jose Luis Sanchez-Menoyo, Youssef Sidhom, Riadh Gouider, Vahid Shaygannejad, Julie Prevost, Ayse Altintas, Yara Dadalti Fragoso, Pamela Ann McCombe, Thor Petersen, Mark Slee, Michael H Barnett, Steve Vucic, Anneke Van Der Walt and Tomas Kalincik in Multiple Sclerosis Journal

Additional file 4 Table S1. Means (SD) for FA at three Time-points using atlas-based ROI and manual ROI. None of the regions, PLIC and CST at pons, showed significant differences overtime.

Supplemental material, MSJ926955_STROBE_checklist for Disability outcomes of early cerebellar and brainstem symptoms in multiple sclerosis by Minh Le, Charles Malpas, Sifat Sharmin, Dana Horáková, Eva Havrdova, Maria Trojano, Guillermo Izquierdo, Sara Eichau, Serkan Ozakbas, Alessandra Lugaresi, Alexandre Prat, Marc Girard, Pierre Duquette, Catherine Larochelle, Raed Alroughani, Roberto Bergamaschi, Patrizia Sola, Diana Ferraro, Pierre Grammond, Francois Grand’ Maison, Murat Terzi, Cavit Boz, Raymond Hupperts, Helmut Butzkueven, Eugenio Pucci, Franco Granella, Vincent Van Pesch, Aysun Soysal, Bassem I. Yamout, Jeannette Lechner-Scott, Daniele LA Spitaleri, Radek Ampapa, Recai Turkoglu, Gerardo Iuliano, Cristina Ramo-Tello, Jose Luis Sanchez-Menoyo, Youssef Sidhom, Riadh Gouider, Vahid Shaygannejad, Julie Prevost, Ayse Altintas, Yara Dadalti Fragoso, Pamela Ann McCombe, Thor Petersen, Mark Slee, Michael H Barnett, Steve Vucic, Anneke Van Der Walt and Tomas Kalincik in Multiple Sclerosis Journal

Supplemental material, MSJ926955_appendix_2 for Disability outcomes of early cerebellar and brainstem symptoms in multiple sclerosis by Minh Le, Charles Malpas, Sifat Sharmin, Dana Horáková, Eva Havrdova, Maria Trojano, Guillermo Izquierdo, Sara Eichau, Serkan Ozakbas, Alessandra Lugaresi, Alexandre Prat, Marc Girard, Pierre Duquette, Catherine Larochelle, Raed Alroughani, Roberto Bergamaschi, Patrizia Sola, Diana Ferraro, Pierre Grammond, Francois Grand’ Maison, Murat Terzi, Cavit Boz, Raymond Hupperts, Helmut Butzkueven, Eugenio Pucci, Franco Granella, Vincent Van Pesch, Aysun Soysal, Bassem I. Yamout, Jeannette Lechner-Scott, Daniele LA Spitaleri, Radek Ampapa, Recai Turkoglu, Gerardo Iuliano, Cristina Ramo-Tello, Jose Luis Sanchez-Menoyo, Youssef Sidhom, Riadh Gouider, Vahid Shaygannejad, Julie Prevost, Ayse Altintas, Yara Dadalti Fragoso, Pamela Ann McCombe, Thor Petersen, Mark Slee, Michael H Barnett, Steve Vucic, Anneke Van Der Walt and Tomas Kalincik in Multiple Sclerosis Journal

Additional file 5 Table S2. FA averaged mean of ROIs in both methods.

Supplemental material, MSJ936823_supplement for Prediction of on-treatment disability worsening in RRMS with the MAGNIMS score by Amy Kunchok, Jeannette Lechner-Scott, Franco Granella, Maria Trojano, Raed Alroughani, Patrizia Sola, Diana Ferraro, Alessandra Lugaresi, Marco Onofrj, Serkan Ozakbas, Guillermo Izquierdo, Pierre Grammond, Jose Luis Sanchez-Menoyo, Bart Van Wijmeersch, Cavit Boz, Eugenio Pucci, Pamela McCombe, Francois Grand’Maison, Daniele Spitaleri, Steve Vucic, Raymond Hupperts, Vilija Jokubaitis, Maria Pia Sormani, Helmut Butzkueven and Tomas Kalincik in Multiple Sclerosis Journal

Supplemental material, MSJ868990_online_supplement for Risk of secondary progressive multiple sclerosis: A longitudinal study by Adam Fambiatos, Vilija Jokubaitis, Dana Horakova, Eva Kubala Havrdova, Maria Trojano, Alexandre Prat, Marc Girard, Pierre Duquette, Alessandra Lugaresi, Guillermo Izquierdo, Francois Grand’Maison, Pierre Grammond, Patrizia Sola, Diana Ferraro, Raed Alroughani, Murat Terzi, Raymond Hupperts, Cavit Boz, Jeannette Lechner-Scott, Eugenio Pucci, Roberto Bergamaschi, Vincent Van Pesch, Serkan Ozakbas, Franco Granella, Recai Turkoglu, Gerardo Iuliano, Daniele Spitaleri, Pamela McCombe, Claudio Solaro, Mark Slee, Radek Ampapa, Aysun Soysal, Thor Petersen, Jose Luis Sanchez-Menoyo, Freek Verheul, Julie Prevost, Youssef Sidhom, Bart Van Wijmeersch, Steve Vucic, Edgardo Cristiano, Maria Laura Saladino, Norma Deri, Michael Barnett, Javier Olascoaga, Fraser Moore, Olga Skibina, Orla Gray, Yara Fragoso, Bassem Yamout, Cameron Shaw, Bhim Singhal, Neil Shuey, Suzanne Hodgkinson, Ayse Altintas, Talal Al-Harbi, Tunde Csepany, Bruce Taylor, Jordana Hughes, Jae-Kwan Jun, Anneke van der Walt, Tim Spelman, Helmut Butzkueven and Tomas Kalincik in Multiple Sclerosis Journal

OBJECTIVE: To identify predictors of 10-year Expanded Disability Status Scale (EDSS) change after treatment initiation in patients with relapse-onset multiple sclerosis.METHODS: Using data obtained from MSBase, we defined baseline as the date of first injectable therapy initiation. Patients need only have remained on injectable therapy for 1 day and were monitored on any approved disease-modifying therapy, or no therapy thereafter. Median EDSS score changes over a 10-year period were determined. Predictors of EDSS change were then assessed using median quantile regression analysis. Sensitivity analyses were further performed.RESULTS: We identified 2,466 patients followed up for at least 10 years reporting post-baseline disability scores. Patients were treated an average 83% of their follow-up time. EDSS scores increased by a median 1 point (interquartile range = 0-2) at 10 years post-baseline. Annualized relapse rate was highly predictive of increases in median EDSS over 10 years (coeff = 1.14, p = 1.9 × 10(-22) ). On-therapy relapses carried greater burden than off-therapy relapses. Cumulative treatment exposure was independently associated with lower EDSS at 10 years (coeff = -0.86, p = 1.3 × 10(-9) ). Furthermore, pregnancies were also independently associated with lower EDSS scores over the 10-year observation period (coeff = -0.36, p = 0.009).INTERPRETATION: We provide evidence of long-term treatment benefit in a large registry cohort, and provide evidence of long-term protective effects of pregnancy against disability accrual. We demonstrate that high annualized relapse rate, particularly on-treatment relapse, is an indicator of poor prognosis. Ann Neurol 2016;80:89-100.

Murine studies show no alemtuzumab-related teratogenicity, but no controlled human clinical studies of alemtuzumab in pregnancy exist. In phase 2 (CAMMS223 [NCT00050778]) and phase 3 (CARE-MS I [NCT00530348], CARE-MS II [NCT00548405]) studies, patients received 2 annual alemtuzumab courses. Two extension studies provided longer-term evaluation (NCT00930553; TOPAZ [NCT02255656]). Pregnant/lactating patients were ineligible for further treatment but were followed up for safety. As of 1 April 2017, 248 pregnancies occurred in 156/972 alemtuzumab-treated female patients (mean [SD] age at conception, 32.5 [4.4] years; mean [SD] time from last alemtuzumab dose to conception, 33.5 [22.6] months; 16 within 4 months of dosing), with 218 completed, 14 ongoing, and 16 with unknown outcomes. Of completed pregnancies with known outcomes, 147 (67%) were live births with no congenital abnormalities or birth defects. There were 48 (22%) spontaneous abortions, 22 (10%) elective abortions, and 1 (0.5%) stillbirth. To date, there has been no signal for teratogenicity. Incidence of spontaneous abortions was comparable with treatment-naive MS patients (5%–21%) and the general population (17%–22%). Real-world data are currently collected by the International Lemtrada Pregnancy Exposure Registry, a prospective, non-interventional, observational safety study enrolling patients in ≥19 countries who become pregnant within 4 months of alemtuzumab exposure.Study Support: Sanofi.

In patients suffering multiple sclerosis activity despite treatment with interferon β or glatiramer acetate, clinicians often switch therapy to either natalizumab or fingolimod. However, no studies have directly compared the outcomes of switching to either of these agents.Using MSBase, a large international, observational, prospectively acquired cohort study, we identified patients with relapsing-remitting multiple sclerosis experiencing relapses or disability progression within the 6 months immediately preceding switch to either natalizumab or fingolimod. Quasi-randomization with propensity score-based matching was used to select subpopulations with comparable baseline characteristics. Relapse and disability outcomes were compared in paired, pairwise-censored analyses.Of the 792 included patients, 578 patients were matched (natalizumab, n = 407; fingolimod, n = 171). Mean on-study follow-up was 12 months. The annualized relapse rates decreased from 1.5 to 0.2 on natalizumab and from 1.3 to 0.4 on fingolimod, with 50% relative postswitch difference in relapse hazard (p = 0.002). A 2.8 times higher rate of sustained disability regression was observed after the switch to natalizumab in comparison to fingolimod (p 0.001). No difference in the rate of sustained disability progression events was observed between the groups. The change in overall disability burden (quantified as area under the disability-time curve) differed between natalizumab and fingolimod (-0.12 vs 0.04 per year, respectively, p 0.001).This study suggests that in active multiple sclerosis during treatment with injectable disease-modifying therapies, switching to natalizumab is more effective than switching to fingolimod in reducing relapse rate and short-term disability burden.

In multiple sclerosis, treatment start or switch is prompted by evidence of disease activity. Whilst immunomodulatory therapies reduce disease activity, the time required to attain maximal effect is unclear. In this study we aimed to develop a method that allows identification of the time to manifest fully and clinically the effect of multiple sclerosis treatments ('therapeutic lag') on clinical disease activity represented by relapses and progression-of-disability events. Data from two multiple sclerosis registries, MSBase (multinational) and OFSEP (French), were used. Patients diagnosed with multiple sclerosis, minimum 1-year exposure to treatment, minimum 3-year pretreatment follow-up and yearly review were included in the analysis. For analysis of disability progression, all events in the subsequent 5-year period were included. Density curves, representing incidence of relapses and 6-month confirmed progression events, were separately constructed for each sufficiently represented therapy. Monte Carlo simulations were performed to identify the first local minimum of the first derivative after treatment start; this point represented the point of stabilization of treatment effect, after the maximum treatment effect was observed. The method was developed in a discovery cohort (MSBase), and externally validated in a separate, non-overlapping cohort (OFSEP). A merged MSBase-OFSEP cohort was used for all subsequent analyses. Annualized relapse rates were compared in the time before treatment start and after the stabilization of treatment effect following commencement of each therapy. We identified 11 180 eligible treatment epochs for analysis of relapses and 4088 treatment epochs for disability progression. External validation was performed in four therapies, with no significant difference in the bootstrapped mean differences in therapeutic lag duration between registries. The duration of therapeutic lag for relapses was calculated for 10 therapies and ranged between 12 and 30 weeks. The duration of therapeutic lag for disability progression was calculated for seven therapies and ranged between 30 and 70 weeks. Significant differences in the pre- versus post-treatment annualized relapse rate were present for all therapies apart from intramuscular interferon beta-1a. In conclusion we have developed, and externally validated, a method to objectively quantify the duration of therapeutic lag on relapses and disability progression in different therapies in patients more than 3 years from multiple sclerosis onset. Objectively defined periods of expected therapeutic lag allows insights into the evaluation of treatment response in randomized clinical trials and may guide clinical decision-making in patients who experience early on-treatment disease activity. This method will subsequently be applied in studies that evaluate the effect of patient and disease characteristics on therapeutic lag. This study was supported by the EDMUS Foundation, Biogen and NHMRC (1140766, 1129189, 1157717). I.R. is supported by a MSIF-ARSEP McDonald fellowship grant and a Melbourne Research Scholarship. The MSBase Foundation is a not-for-profit organization that receives support from Biogen, Novartis, Merck, Roche, Teva and Sanofi Genzyme. The Observatoire Francais de la Sclerose en Plaques (OFSEP) is supported by a grant provided by the French State and handled by the 'Agence Nationale de la Recherche,' within the framework of the 'Investments for the Future' program, under the reference ANR-10-COHO-002, by the Eugene Devic EDMUS Foundation against multiple sclerosis and by the ARSEP Foundation. The study was conducted separately and apart from the guidance of the sponsors. Kalincik, T (corresponding author), Univ Melbourne, Dept Med, CORe, 300 Grattan St, Melbourne, Vic 3050, Australia. tomas.kalincik@unimelb.edu.au

In multiple sclerosis, treatment start or switch is prompted by evidence of disease activity. Whilst immunomodulatory therapies reduce disease activity, the time required to attain maximal effect is unclear. In this study we aimed to develop a method that allows identification of the time to manifest fully and clinically the effect of multiple sclerosis treatments ('therapeutic lag') on clinical disease activity represented by relapses and progression-of-disability events. Data from two multiple sclerosis registries, MSBase (multinational) and OFSEP (French), were used. Patients diagnosed with multiple sclerosis, minimum 1-year exposure to treatment, minimum 3-year pretreatment follow-up and yearly review were included in the analysis. For analysis of disability progression, all events in the subsequent 5-year period were included. Density curves, representing incidence of relapses and 6-month confirmed progression events, were separately constructed for each sufficiently represented therapy. Monte Carlo simulations were performed to identify the first local minimum of the first derivative after treatment start; this point represented the point of stabilization of treatment effect, after the maximum treatment effect was observed. The method was developed in a discovery cohort (MSBase), and externally validated in a separate, non-overlapping cohort (OFSEP). A merged MSBase-OFSEP cohort was used for all subsequent analyses. Annualized relapse rates were compared in the time before treatment start and after the stabilization of treatment effect following commencement of each therapy. We identified 11 180 eligible treatment epochs for analysis of relapses and 4088 treatment epochs for disability progression. External validation was performed in four therapies, with no significant difference in the bootstrapped mean differences in therapeutic lag duration between registries. The duration of therapeutic lag for relapses was calculated for 10 therapies and ranged between 12 and 30 weeks. The duration of therapeutic lag for disability progression was calculated for seven therapies and ranged between 30 and 70 weeks. Significant differences in the pre- versus post-treatment annualized relapse rate were present for all therapies apart from intramuscular interferon beta-1a. In conclusion we have developed, and externally validated, a method to objectively quantify the duration of therapeutic lag on relapses and disability progression in different therapies in patients more than 3 years from multiple sclerosis onset. Objectively defined periods of expected therapeutic lag allows insights into the evaluation of treatment response in randomized clinical trials and may guide clinical decision-making in patients who experience early on-treatment disease activity. This method will subsequently be applied in studies that evaluate the effect of patient and disease characteristics on therapeutic lag.

Objective: This study evaluated the effect of relapse phenotype on disability accumulation in multiple sclerosis. Methods: Analysis of prospectively collected data was conducted in 19,504 patients with relapse-onset multiple sclerosis and minimum 1-year prospective follow-up from the MSBase cohort study. Multivariable linear regression models assessed associations between relapse incidence, phenotype and changes in disability (quantified with Expanded Disability Status Scale and its Functional System scores). Sensitivity analyses were conducted. Results: In 34,858 relapses recorded during 136,462 patient-years (median follow-up 5.9 years), higher relapse incidence was associated with greater disability accumulation (β = 0.16, p Conclusion: Relapses are associated with accumulation of neurological disability. Relapses in pyramidal, cerebellar and bowel/bladder systems have the greatest association with disability change. Therefore, prevention of these relapses is an important objective of disease-modifying therapy. The differential impact of relapse phenotypes on disability outcomes could influence management of treatment failure in multiple sclerosis.