Publications by authors named "Cristina Ramo-Tello"

34 Publications

Vitamin D3-Induced Tolerogenic Dendritic Cells Modulate the Transcriptomic Profile of T CD4 Cells Towards a Functional Hyporesponsiveness.

Front Immunol 2020 20;11:599623. Epub 2021 Jan 20.

Division of Immunology, LCMN, Germans Trias i Pujol University Hospital and Research Institute, Barcelona, Spain.

The use of autologous tolerogenic dendritic cells (tolDC) has become a promising alternative for the treatment of autoimmune diseases. Among the different strategies available, the use of vitamin D3 for the generation of tolDC (vitD3-tolDC) constitutes one of the most robust approaches due to their immune regulatory properties, which are currently being tested in clinical trials. However, the mechanisms that vitD3-tolDC trigger for the induction of tolerance remain elusive. For this reason, we performed a full phenotypical, functional, and transcriptomic characterization of T cells upon their interaction with autologous, antigen-specific vitD3-tolDC. We observed a strong antigen-specific reduction of T cell proliferation, combined with a decrease in the relative prevalence of T1 subpopulations and IFN- production. The analysis of the transcriptomic profile of T CD4 cells evidenced a significant down-modulation of genes involved in cell cycle and cell response to mainly pro-inflammatory immune-related stimuli, highlighting the role of gene as a potential biomarker of these processes. Consequently, our results show the induction of a strong antigen-specific hyporesponsiveness combined with a reduction on the T1 immune profile of T cells upon their interaction with vitD3-tolDC, which manifests the regulatory properties of these cells and, therefore, their therapeutic potential in the clinic.
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http://dx.doi.org/10.3389/fimmu.2020.599623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856150PMC
January 2021

Effect of Disease-Modifying Therapy on Disability in Relapsing-Remitting Multiple Sclerosis Over 15 Years.

Neurology 2021 02 28;96(5):e783-e797. Epub 2020 Dec 28.

From CORe (T.K., I.D., S.S., C.M.), Department of Medicine, University of Melbourne; MS Centre (T.K., I.D., S.S., C.M.), Department of Neurology, Royal Melbourne Hospital, Australia; Karolinska Institute (T.S.), Stockholm, Sweden; Department of Neuroscience (T.S., V.J., A.v.d.W., O.S., H.B.), Central Clinical School, Monash University, Melbourne; Burnet Institute (T.S.), Melbourne, Australia; Department of Neurology and Center of Clinical Neuroscience (D.H., E.K.H.), General University Hospital and Charles University in Prague, Czech Republic; Department of Basic Medical Sciences, Neuroscience and Sense Organs (M. Trojano), University of Bari, Italy; Hospital Universitario Virgen Macarena (G.I.), Sevilla, Spain; Department of Neuroscience, Imaging and Clinical Sciences (A.L.), University "G. d'Annunzio," Chieti; Department of Biomedical and Neuromotor Sciences (A.L.), University of Bologna, IRCCS Istituto delle Scienze Neurologiche di Bologna, Italy; Hopital Notre Dame (A.P., M.G., P.D.), Montreal; CHUM and Universite de Montreal (A.P., M.G., P.D.); CISSS Chaudière-Appalache (P.G.), Levis, Canada; Department of Neurology (V.J., A.v.d.W., O.S., H.B.), Alfred Hospital, Melbourne, Australia; Neuro Rive-Sud (F. Grand'Maison), Quebec, Canada; Department of Neuroscience (P.S., D.F.), Azienda Ospedaliera Universitaria, Modena, Italy; Isfahan University of Medical Sciences (V.S.), Isfahan, Iran; Amiri Hospital (R. Alroughani), Kuwait City, Kuwait; Zuyderland Ziekenhuis (R.H.), Sittard, the Netherlands; Medical Faculty (M. Terzi), 19 Mayis University, Samsun; KTU Medical Faculty Farabi Hospital (C.B.), Karadeniz Technical University, Trabzon, Turkey; School of Medicine and Public Health (J.L.-S.), University Newcastle; Department of Neurology (J.L.-S.), John Hunter Hospital, Newcastle, Australia; UOC Neurologia (E.P.), Azienda Sanitaria Unica Regionale Marche-AV3, Macerata, Italy; Cliniques Universitaires Saint-Luc (V.V.P.), Brussels, Belgium; University of Parma (F. Granella); C. Mondino National Neurological Institute (R.B.), Pavia; Azienda Ospedaliera di Rilievo Nazionale San Giuseppe Moscati Avellino (D.S.), Italy; Flinders University (M. Slee), Adelaide; Westmead Hospital (S.V.), Sydney, Australia; Nemocnice Jihlava (R. Ampapa), Czech Republic; University of Queensland (P.M.), Brisbane; Royal Brisbane and Women's Hospital (P.M.), Brisbane, Australia; Hospital Germans Trias i Pujol (C.R.-T.), Badalona, Spain; CSSS Saint-Jérôme (J.P.), Canada; Hospital Universitario Donostia (J.O.), Paseo de Begiristain, San Sebastián, Spain; Hospital Italiano (E.C.), Buenos Aires, Argentina; Brain and Mind Centre (M.B.), University of Sydney, Australia; INEBA-Institute of Neuroscience Buenos Aires (M.L.S.), Argentina; Hospital de Galdakao-Usansolo (J.L.S.-M.), Galdakao, Spain; Liverpool Hospital (S. Hodgkinson), Sydney, Australia; Jahn Ferenc Teaching Hospital (C.R.), Budapest, Hungary; Craigavon Area Hospital (S. Hughes), UK; Jewish General Hospital (F.M.), Montreal, Canada; Deakin University (C.S.), Geelong; Monash Medical Centre (E.B.), Melbourne, Australia; South East Trust (O.G.), Belfast, UK; Perron Institute (A.K.), University of Western Australia, Nedlands; Institute of Immunology and Infectious Diseases (A.K.), Murdoch University; Sir Charles Gairdner Hospital (A.K.), Perth, Australia; Department of Neurology (T.C.), Faculty of Medicine, University of Debrecen, Hungary; Bombay Hospital Institute of Medical Sciences (B.S.), Mumbai, India; St Vincents Hospital (N.S.), Fitzroy, Melbourne, Australia; Veszprém Megyei Csolnoky Ferenc Kórház zrt (I.P.), Veszprem, Hungary; Royal Hobart Hospital (B.T.), Australia; Semmelweis University Budapest (M. Simo), Hungary; Central Military Emergency University Hospital (C.-A.S.), Bucharest; Titu Maiorescu University (C.-A.S.), Bucharest, Romania; BAZ County Hospital (A.S.), Miskolc, Hungary; and Box Hill Hospital (H.B.), Melbourne, Australia.

Objective: To test the hypothesis that immunotherapy prevents long-term disability in relapsing-remitting multiple sclerosis (MS), we modeled disability outcomes in 14,717 patients.

Methods: We studied patients from MSBase followed for ≥1 year, with ≥3 visits, ≥1 visit per year, and exposed to MS therapy, and a subset of patients with ≥15-year follow-up. Marginal structural models were used to compare the cumulative hazards of 12-month confirmed increase and decrease in disability, Expanded Disability Status Scale (EDSS) step 6, and the incidence of relapses between treated and untreated periods. Marginal structural models were continuously readjusted for patient age, sex, pregnancy, date, disease course, time from first symptom, prior relapse history, disability, and MRI activity.

Results: A total of 14,717 patients were studied. During the treated periods, patients were less likely to experience relapses (hazard ratio 0.60, 95% confidence interval [CI] 0.43-0.82, = 0.0016), worsening of disability (0.56, 0.38-0.82, = 0.0026), and progress to EDSS step 6 (0.33, 0.19-0.59, = 0.00019). Among 1,085 patients with ≥15-year follow-up, the treated patients were less likely to experience relapses (0.59, 0.50-0.70, = 10) and worsening of disability (0.81, 0.67-0.99, = 0.043).

Conclusion: Continued treatment with MS immunotherapies reduces disability accrual by 19%-44% (95% CI 1%-62%), the risk of need of a walking aid by 67% (95% CI 41%-81%), and the frequency of relapses by 40-41% (95% CI 18%-57%) over 15 years. This study provides evidence that disease-modifying therapies are effective in improving disability outcomes in relapsing-remitting MS over the long term.

Classification Of Evidence: This study provides Class IV evidence that, for patients with relapsing-remitting MS, long-term exposure to immunotherapy prevents neurologic disability.
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http://dx.doi.org/10.1212/WNL.0000000000011242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884998PMC
February 2021

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

Disability outcomes of early cerebellar and brainstem symptoms in multiple sclerosis.

Mult Scler 2021 Apr 15;27(5):755-766. Epub 2020 Jun 15.

CORe, Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia; Department of Neurology, The Royal Melbourne Hospital, Melbourne, VIC, Australia.

Background: Cerebellar and brainstem symptoms are common in early stages of multiple sclerosis (MS) yet their prognostic values remain unclear.

Objective: The aim of this study was to investigate long-term disability outcomes in patients with early cerebellar and brainstem symptoms.

Methods: This study used data from MSBase registry. Patients with early cerebellar/brainstem presentations were identified as those with cerebellar/brainstem relapse(s) or functional system score ⩾ 2 in the initial 2 years. Early pyramidal presentation was chosen as a comparator. Andersen-Gill models were used to compare cumulative hazards of (1) disability progression events and (2) relapses between patients with and without early cerebellar/brainstem symptoms. Mixed effect models were used to estimate the associations between early cerebellar/brainstem presentations and expanded disability status scale (EDSS) scores.

Results: The study cohort consisted of 10,513 eligible patients, including 2723 and 3915 patients with early cerebellar and brainstem symptoms, respectively. Early cerebellar presentation was associated with greater hazard of progression events (HR = 1.37,  < 0.001) and EDSS (β = 0.16,  < 0.001). Patients with early brainstem symptoms had lower hazard of progression events (HR = 0.89,  = 0.01) and EDSS (β = -0.06,  < 0.001). Neither presentation was associated with changes in relapse risk.

Conclusion: Early cerebellar presentation is associated with unfavourable outcomes, while early brainstem presentation is associated with favourable prognosis. These presentations may be used as MS prognostic markers and guide therapeutic approach.
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http://dx.doi.org/10.1177/1352458520926955DOI Listing
April 2021

Early clinical markers of aggressive multiple sclerosis.

Brain 2020 05;143(5):1400-1413

CORe Unit, Department of Medicine, University of Melbourne, Melbourne, Australia.

Patients with the 'aggressive' form of multiple sclerosis accrue disability at an accelerated rate, typically reaching Expanded Disability Status Score (EDSS) ≥ 6 within 10 years of symptom onset. Several clinicodemographic factors have been associated with aggressive multiple sclerosis, but less research has focused on clinical markers that are present in the first year of disease. The development of early predictive models of aggressive multiple sclerosis is essential to optimize treatment in this multiple sclerosis subtype. We evaluated whether patients who will develop aggressive multiple sclerosis can be identified based on early clinical markers. We then replicated this analysis in an independent cohort. Patient data were obtained from the MSBase observational study. Inclusion criteria were (i) first recorded disability score (EDSS) within 12 months of symptom onset; (ii) at least two recorded EDSS scores; and (iii) at least 10 years of observation time, based on time of last recorded EDSS score. Patients were classified as having 'aggressive multiple sclerosis' if all of the following criteria were met: (i) EDSS ≥ 6 reached within 10 years of symptom onset; (ii) EDSS ≥ 6 confirmed and sustained over ≥6 months; and (iii) EDSS ≥ 6 sustained until the end of follow-up. Clinical predictors included patient variables (sex, age at onset, baseline EDSS, disease duration at first visit) and recorded relapses in the first 12 months since disease onset (count, pyramidal signs, bowel-bladder symptoms, cerebellar signs, incomplete relapse recovery, steroid administration, hospitalization). Predictors were evaluated using Bayesian model averaging. Independent validation was performed using data from the Swedish Multiple Sclerosis Registry. Of the 2403 patients identified, 145 were classified as having aggressive multiple sclerosis (6%). Bayesian model averaging identified three statistical predictors: age > 35 at symptom onset, EDSS ≥ 3 in the first year, and the presence of pyramidal signs in the first year. This model significantly predicted aggressive multiple sclerosis [area under the curve (AUC) = 0.80, 95% confidence intervals (CIs): 0.75, 0.84, positive predictive value = 0.15, negative predictive value = 0.98]. The presence of all three signs was strongly predictive, with 32% of such patients meeting aggressive disease criteria. The absence of all three signs was associated with a 1.4% risk. Of the 556 eligible patients in the Swedish Multiple Sclerosis Registry cohort, 34 (6%) met criteria for aggressive multiple sclerosis. The combination of all three signs was also predictive in this cohort (AUC = 0.75, 95% CIs: 0.66, 0.84, positive predictive value = 0.15, negative predictive value = 0.97). Taken together, these findings suggest that older age at symptom onset, greater disability during the first year, and pyramidal signs in the first year are early indicators of aggressive multiple sclerosis.
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http://dx.doi.org/10.1093/brain/awaa081DOI Listing
May 2020

Tolerogenic dendritic cell-based treatment for multiple sclerosis (MS): a harmonised study protocol for two phase I clinical trials comparing intradermal and intranodal cell administration.

BMJ Open 2019 09 9;9(9):e030309. Epub 2019 Sep 9.

Multiple Sclerosis Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Badalona, Spain

Introduction: Based on the advances in the treatment of multiple sclerosis (MS), currently available disease-modifying treatments (DMT) have positively influenced the disease course of MS. However, the efficacy of DMT is highly variable and increasing treatment efficacy comes with a more severe risk profile. Hence, the unmet need for safer and more selective treatments remains. Specifically restoring immune tolerance towards myelin antigens may provide an attractive alternative. In this respect, antigen-specific tolerisation with autologous tolerogenic dendritic cells (tolDC) is a promising approach.

Methods And Analysis: Here, we will evaluate the clinical use of tolDC in a well-defined population of MS patients in two phase I clinical trials. In doing so, we aim to compare two ways of tolDC administration, namely intradermal and intranodal. The cells will be injected at consecutive intervals in three cohorts receiving incremental doses of tolDC, according to a best-of-five design. The primary objective is to assess the safety and feasibility of tolDC administration. For safety, the number of adverse events including MRI and clinical outcomes will be assessed. For feasibility, successful production of tolDC will be determined. Secondary endpoints include clinical and MRI outcome measures. The patients' immune profile will be assessed to find presumptive evidence for a tolerogenic effect in vivo.

Ethics And Dissemination: Ethics approval was obtained for the two phase I clinical trials. The results of the trials will be disseminated in a peer-reviewed journal, at scientific conferences and to patient associations.

Trial Registration Numbers: NCT02618902 and NCT02903537; EudraCT numbers: 2015-002975-16 and 2015-003541-26.
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http://dx.doi.org/10.1136/bmjopen-2019-030309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738722PMC
September 2019

Th1Th17 Lymphocyte Subpopulation as a Predictive Biomarker of Disease Activity in Multiple Sclerosis Patients under Dimethyl Fumarate or Fingolimod Treatment.

Mediators Inflamm 2019 26;2019:8147803. Epub 2019 Jun 26.

Multiple Sclerosis Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain.

Peripheral blood biomarkers able to predict disease activity in multiple sclerosis (MS) patients have not been identified yet. Here, we analyzed the immune phenotype of T lymphocyte subpopulations in peripheral blood samples from 66 RRMS patients under DMF ( = 22) or fingolimod ( = 44) treatment, by flow cytometry. A correlation study between the percentage and absolute cell number of each lymphocyte subpopulation with the presence of relapses or new MRI lesions during 12-month follow-up was performed. Patients who had undergone relapses showed at baseline higher percentage of Th1 cells (relapsed: 11.60 ± 4.17%. nonrelapsed: 9.25 ± 3.17%, < 0.05) and Th1Th17 cells (relapsed: 15.65 ± 6.15%. nonrelapsed: 10.14 ± 4.05%, < 0.01) before initiating DMF or fingolimod treatment. Kaplan-Meier analysis revealed that patients with Th1Th17 (CD4CCR7CD45RACCR6CXCR3) cells > 11.48% had a 50% relapse-free survival compared to patients with Th1Th17cells < 11.48% whose relapse-free survival was 88% ( = 0.013, log-rank test). Additionally, a high percentage of Th1Th17 cells was also found in patients with MRI activity (MRI activity: 14.02 ± 5.87%. no MRI activity: 9.82 ± 4.06%, < 0.01). Our results suggest that the percentage of Th1Th17 lymphocytes at baseline is a predictive biomarker of activity during the first 12 months of treatment, regardless of the treatment.
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http://dx.doi.org/10.1155/2019/8147803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617925PMC
January 2020

and Are Biomarkers of Vitamin D3-Induced Tolerogenic Dendritic Cells in Multiple Sclerosis Patients.

Front Immunol 2019 19;10:1251. Epub 2019 Jun 19.

Division of Immunology, LCMN, Germans Trias i Pujol University Hospital and Research Institute, Barcelona, Spain.

The administration of autologous tolerogenic dendritic cells (tolDC) has become a promising alternative for the treatment of autoimmune diseases, such as multiple sclerosis (MS). Specifically, the use of vitamin D3 for the generation of tolDC (vitD3-tolDC) constitutes one of the most widely studied approaches, as it has evidenced significant immune regulatory properties, both and . In this article, we generated human vitD3-tolDC from monocytes from healthy donors and MS patients, characterized in both cases by a semi-mature phenotype, secretion of IL-10 and inhibition of allogeneic lymphocyte proliferation. Additionally, we studied their transcriptomic profile and selected a number of differentially expressed genes compared to control mature and immature dendritic cells for their analysis. Among them, qPCR results validated and genes as biomarkers of vitD3-tolDC in both healthy donors and MS patients. Furthermore, we constructed a network of protein interactions based on the literature, which manifested that and genes are both closely connected between them and involved in immune-related functions. In conclusion, this study evidences that and constitute robust and potentially functional biomarkers of the generation of vitD3-tolDC, opening the window for their use as quality controls in clinical trials for MS.
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http://dx.doi.org/10.3389/fimmu.2019.01251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598738PMC
September 2020

Optimal response to dimethyl fumarate is mediated by a reduction of Th1-like Th17 cells after 3 months of treatment.

CNS Neurosci Ther 2019 09 7;25(9):995-1005. Epub 2019 May 7.

Immunology Division, LCMN, Germans Trias i Pujol University Hospital and Research Institute, Campus Can Ruti, Badalona, Spain.

Aim: Dimethyl fumarate (DMF) is one of the most promising therapies for relapsing-remitting multiple sclerosis (RRMS) patients since it has shown immunomodulatory and neuroprotective effects. However, a percentage of RRMS patients do not exhibit an optimal response to DMF. The objective of this study was to identify early biomarkers of treatment response by analyzing changes in peripheral leukocyte subpopulations directly in whole blood samples.

Methods: A longitudinal and prospective study analyzing peripheral blood leukocyte subpopulations in 22 RRMS patients before initiating DMF treatment (baseline) and at 1, 3, 6, and 12 months of follow-up was performed. Differences between no evidence of disease activity (NEDA) and ongoing disease activity (ODA) patients were analyzed.

Results: The beneficial effect of DMF was associated with a specific depletion of memory CD4 and CD8 T lymphocytes and B cells. Importantly, only NEDA patients showed (a) a shift from a pro- to an antiinflammatory profile, with an increase of Th2 cells and a decrease of Th1-like Th17 lymphocytes; and (b) an increase of regulatory CD56 NK cells.

Conclusion: The optimal response to DMF is mediated by a shift to antiinflammatory and immunoregulatory profile, which puts forward Th1-like Th17 lymphocytes as a potential early biomarker of treatment response.
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http://dx.doi.org/10.1111/cns.13142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698982PMC
September 2019

Comparison of fingolimod, dimethyl fumarate and teriflunomide for multiple sclerosis.

J Neurol Neurosurg Psychiatry 2019 04 13;90(4):458-468. Epub 2019 Jan 13.

Central Clinical School, Monash University, Melbourne, Victoria, Australia.

Objective: Oral immunotherapies have become a standard treatment in relapsing-remitting multiple sclerosis. Direct comparison of their effect on relapse and disability is needed.

Methods: We identified all patients with relapsing-remitting multiple sclerosis treated with teriflunomide, dimethyl fumarate or fingolimod, with minimum 3-month treatment persistence and disability follow-up in the global MSBase cohort study. Patients were matched using propensity scores. Three pairwise analyses compared annualised relapse rates and hazards of disability accumulation, disability improvement and treatment discontinuation (analysed with negative binomial models and weighted conditional survival models, with pairwise censoring).

Results: The eligible cohorts consisted of 614 (teriflunomide), 782 (dimethyl fumarate) or 2332 (fingolimod) patients, followed over the median of 2.5 years. Annualised relapse rates were lower on fingolimod compared with teriflunomide (0.18 vs 0.24; p=0.05) and dimethyl fumarate (0.20 vs 0.26; p=0.01) and similar on dimethyl fumarate and teriflunomide (0.19 vs 0.22; p=0.55). No differences in disability accumulation (p≥0.59) or improvement (p≥0.14) were found between the therapies. In patients with ≥3-month treatment persistence, subsequent discontinuations were less likely on fingolimod than teriflunomide and dimethyl fumarate (p<0.001). Discontinuation rates on teriflunomide and dimethyl fumarate were similar (p=0.68).

Conclusion: The effect of fingolimod on relapse frequency was superior to teriflunomide and dimethyl fumarate. The effect of the three oral therapies on disability outcomes was similar during the initial 2.5 years on treatment. Persistence on fingolimod was superior to the two comparator drugs.
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http://dx.doi.org/10.1136/jnnp-2018-319831DOI Listing
April 2019

Incidence of pregnancy and disease-modifying therapy exposure trends in women with multiple sclerosis: A contemporary cohort study.

Mult Scler Relat Disord 2019 Feb 3;28:235-243. Epub 2019 Jan 3.

Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia; Department of Neurology, Alfred Hospital, Melbourne, Australia; Department of Medicine (Royal Melbourne Hospital), University of Melbourne, Melbourne, Australia. Electronic address:

Background: Exposure to disease-modifying therapy (DMT) during early pregnancy in women with relapsing-remitting MS (RRMS) may be increasing.

Objective: To retrospectively determine incidence of pregnancy, DMT exposure and pregnancy outcomes in women with RRMS.

Methods: We identified all women with RRMS aged 15-45 years in the MSBase Registry between 2005-2016. Annualised pregnancy incidence rates were calculated using Poisson regression models. DMT exposures and pregnancy outcomes were assessed.

Results: Of 9,098 women meeting inclusion criteria, 1,178 (13%) women recorded 1,521 pregnancies. The annualised incidence rate of pregnancy was 0.042 (95% CI 0.040, 0.045). A total of 635 (42%) reported pregnancies were conceived on DMT, increasing from 27% in 2006 to 62% in 2016. The median duration of DMT exposure during pregnancy was 30 days (IQR: 9, 50). There were a higher number of induced abortions on FDA pregnancy class C/D drugs compared with pregnancy class B and no DMT (p = 0.010); but no differences in spontaneous abortions, term or preterm births.

Conclusions: We report low pregnancy incidence rates, with increasing number of pregnancies conceived on DMT over the past 12-years. The median duration of DMT exposure in pregnancy was relatively short at one month.
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http://dx.doi.org/10.1016/j.msard.2019.01.003DOI Listing
February 2019

Comparative transcriptomic profile of tolerogenic dendritic cells differentiated with vitamin D3, dexamethasone and rapamycin.

Sci Rep 2018 10 8;8(1):14985. Epub 2018 Oct 8.

Germans Trias i Pujol University Hospital and Research Institute, Immunology Division, Badalona, 08916, Spain.

Tolerogenic dendritic cell (tolDC)-based therapies have become a promising approach for the treatment of autoimmune diseases by their potential ability to restore immune tolerance in an antigen-specific manner. However, the broad variety of protocols used to generate tolDC in vitro and their functional and phenotypical heterogeneity are evidencing the need to find robust biomarkers as a key point towards their translation into the clinic, as well as better understanding the mechanisms involved in the induction of immune tolerance. With that aim, in this study we have compared the transcriptomic profile of tolDC induced with either vitamin D3 (vitD3-tolDC), dexamethasone (dexa-tolDC) or rapamycin (rapa-tolDC) through a microarray analysis in 5 healthy donors. The results evidenced that common differentially expressed genes could not be found for the three different tolDC protocols. However, individually, CYP24A1, MUCL1 and MAP7 for vitD3-tolDC; CD163, CCL18, C1QB and C1QC for dexa-tolDC; and CNGA1 and CYP7B1 for rapa-tolDC, constituted good candidate biomarkers for each respective cellular product. In addition, a further gene set enrichment analysis of the data revealed that dexa-tolDC and vitD3-tolDC share several immune regulatory and anti-inflammatory pathways, while rapa-tolDC seem to be playing a totally different role towards tolerance induction through a strong immunosuppression of their cellular processes.
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http://dx.doi.org/10.1038/s41598-018-33248-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175832PMC
October 2018

Association of Inflammation and Disability Accrual in Patients With Progressive-Onset Multiple Sclerosis.

JAMA Neurol 2018 11;75(11):1407-1415

CORe, Department of Medicine, University of Melbourne, Parkville, Victoria, Australia.

Importance: The role of inflammatory disease activity as a determinant of disability in progressive-onset multiple sclerosis (MS) remains contested.

Objective: To examine the association of superimposed relapses in progressive-onset MS on disease outcomes.

Design, Setting, And Participants: Observational cohort study from MSBase, a prospectively collected, international database. Data were collected between January 1995 and February 2017. Analyses began in February 2017. From 44 449 patients at time of extraction, 1419 eligible patients (31.9%) were identified for analysis. Inclusion criteria consisted of primary progressive MS (PPMS) or progressive-relapsing MS (PRMS), adult-onset disease, and minimum data set (including ≥3 visits with disability recorded, ≥3 months between second and last visit). Data were analyzed using multivariable regression models (Andersen-Gill) with mixed effects. Two sensitivity analyses to exclude both relapse-related disability progression and bout-onset progressive MS were performed.

Exposures: Grouped according to presence or absence of relapse, defined as an acute episode of clinical worsening. Quantifiable disability change or correlation on imaging was not required to confirm relapse.

Main Outcomes And Measures: Cumulative hazard of disability progression.

Results: Patients with PRMS were younger than those with PPMS (mean [SD] age, 46 [15] vs 51 [10] years, Cohen d = 0.40) and demonstrated a mean lower Expanded Disability Status Scale score (mean [SD] score, 4.0 [3] vs 4.5 [2.5], Cohen d = 0.28) at inclusion. The ratio of men to women was similar in the PRMS and PPMS groups (252:301 vs 394:472). The overall mean (SD) age was 48 (11) years for men and 50 (10) years for women. Likelihood of confirmed disability progression was lower in patients with superimposed relapses (hazard ratio [HR], 0.83; 95% CI, 0.74-0.94; P = .003). Proportion of follow-up time spent on disease-modifying therapy significantly reduced the hazard of confirmed disability progression in the cohort with relapse (HR, 0.96; 95% CI, 0.94-0.99; P = .01) but not in those without relapse (HR, 1.02; 95% CI, 0.99-1.05; P = .26). When accounting for relapse-related progression, the association of disease-modifying therapy in the cohort with superimposed relapse was no longer observed (HR, 1.10; 95% CI, 0.96-1.24; P = .16).

Conclusions And Relevance: In progressive-onset MS, superimposed relapses are associated with a lower risk of confirmed disability progression. This is most likely attributed to the association of disease-modifying therapy with the prevention of relapse-related disability accrual in patients with superimposed relapse. These findings suggest that inflammatory relapses are an important and modifiable determinant of disability accrual in progressive-onset disease.
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http://dx.doi.org/10.1001/jamaneurol.2018.2109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6248114PMC
November 2018

Predicting therapeutic response to fingolimod treatment in multiple sclerosis patients.

CNS Neurosci Ther 2018 12 15;24(12):1175-1184. Epub 2018 Apr 15.

Immunology Division, Germans Trias i Pujol University Hospital and Research Institute, Barcelona, Spain.

Aims: Fingolimod, an orally active immunomodulatory drug for relapsing-remitting multiple sclerosis (RRMS), sequesters T cells in lymph nodes through functional antagonism of the sphingosine-1-phosphate receptor, reducing the number of potential autoreactive cells that migrate to the central nervous system. However, not all RRMS patients respond to this therapy. Our aim was to test the hypothesis that by immune-monitoring RRMS patient's leukocyte subpopulations it is possible to find biomarkers associated with clinical response to fingolimod.

Methods: Prospective study. Analysis of peripheral blood mononuclear cell subpopulations by multiparametric flow cytometry, at baseline and +1, +3, +6, +12 months of follow-up in 40 RRMS patients starting fingolimod therapy.

Results: Fingolimod treatment induced a severe lymphopenia affecting mainly T and B cells. A relative increase in T (memory T : 3.8 ± 1.0% baseline vs 8.8 ± 4.4% month +1; activated T : 1.5 ± 0.7% baseline vs 3.7 ± 2.1% month +1, P < 0.001) as well as transitional B cells (10.5 ± 12.3% baseline vs 18.7 ± 14.6% month +1, P < 0.001) was observed. Interestingly, lymphocyte subpopulations were already at baseline significantly different in responder patients. The percentage of recent thymic emigrants (RTE) used to stratify fingolimod responder, and no responder patients was the best biomarker (4.0 ± 1.4% vs 7.4 ± 1.9%, respectively [P < 0.001]).

Conclusion: The results support that immune-monitoring of lymphocyte subpopulations in peripheral blood is a promising tool to select RRMS candidate for fingolimod treatment.
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http://dx.doi.org/10.1111/cns.12851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6489963PMC
December 2018

Towards personalized therapy for multiple sclerosis: prediction of individual treatment response.

Brain 2017 Sep;140(9):2426-2443

Department of Neurology, Royal Melbourne Hospital, 300 Grattan St, Melbourne, 3050, Australia.

Timely initiation of effective therapy is crucial for preventing disability in multiple sclerosis; however, treatment response varies greatly among patients. Comprehensive predictive models of individual treatment response are lacking. Our aims were: (i) to develop predictive algorithms for individual treatment response using demographic, clinical and paraclinical predictors in patients with multiple sclerosis; and (ii) to evaluate accuracy, and internal and external validity of these algorithms. This study evaluated 27 demographic, clinical and paraclinical predictors of individual response to seven disease-modifying therapies in MSBase, a large global cohort study. Treatment response was analysed separately for disability progression, disability regression, relapse frequency, conversion to secondary progressive disease, change in the cumulative disease burden, and the probability of treatment discontinuation. Multivariable survival and generalized linear models were used, together with the principal component analysis to reduce model dimensionality and prevent overparameterization. Accuracy of the individual prediction was tested and its internal validity was evaluated in a separate, non-overlapping cohort. External validity was evaluated in a geographically distinct cohort, the Swedish Multiple Sclerosis Registry. In the training cohort (n = 8513), the most prominent modifiers of treatment response comprised age, disease duration, disease course, previous relapse activity, disability, predominant relapse phenotype and previous therapy. Importantly, the magnitude and direction of the associations varied among therapies and disease outcomes. Higher probability of disability progression during treatment with injectable therapies was predominantly associated with a greater disability at treatment start and the previous therapy. For fingolimod, natalizumab or mitoxantrone, it was mainly associated with lower pretreatment relapse activity. The probability of disability regression was predominantly associated with pre-baseline disability, therapy and relapse activity. Relapse incidence was associated with pretreatment relapse activity, age and relapsing disease course, with the strength of these associations varying among therapies. Accuracy and internal validity (n = 1196) of the resulting predictive models was high (>80%) for relapse incidence during the first year and for disability outcomes, moderate for relapse incidence in Years 2-4 and for the change in the cumulative disease burden, and low for conversion to secondary progressive disease and treatment discontinuation. External validation showed similar results, demonstrating high external validity for disability and relapse outcomes, moderate external validity for cumulative disease burden and low external validity for conversion to secondary progressive disease and treatment discontinuation. We conclude that demographic, clinical and paraclinical information helps predict individual response to disease-modifying therapies at the time of their commencement.
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http://dx.doi.org/10.1093/brain/awx185DOI Listing
September 2017

Epidemiology of NMOSD in Catalonia: Influence of the new 2015 criteria in incidence and prevalence estimates.

Mult Scler 2018 12 6;24(14):1843-1851. Epub 2017 Oct 6.

Center of Neuroimmunology, Laboratory of Advanced Imaging in Neuroimmunological Diseases, Hospital Clinic of Barcelona and Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.

Background: Population-based studies on neuromyelitis optica spectrum disorders (NMOSD) are limited, and it is unclear whether the rates have changed with the implementation of the new 2015 criteria.

Objectives: To estimate the incidence and prevalence of NMOSD in Catalonia (Spain), using both the 2006 and the 2015 criteria.

Methods: In this clinic-based retrospective study, patients diagnosed with NMOSD between 2006 and 2015 were identified using multiple sources, including direct contact to all Catalan hospitals, identification of cases through the Catalan Health Surveillance System, and registry of antibodies to aquaporin-4 (AQP4-IgG) and myelin oligodendrocyte glycoprotein (MOG-IgG) in a reference laboratory. The incidence rate was calculated for the period 1 January 2006-1 January 2016 and prevalence for the date 1 January 2016.

Results: We identified 74 patients (by the 2015 criteria). Most patients were Caucasian (81%), and female (76%) with a median age at disease onset of 42 years (range, 10-76 years). In total, 54 (73%) patients were positive for AQP4-IgG, 11 (15%) double-seronegative, and 9 (12%) MOG-IgG-positive. Rates of incidence and prevalence (0.63/1,000,000 person-years and 0.89/100,000, respectively) were 1.5-fold higher than those reported by the 2006 criteria. Lowest rates were seen in children and elder people and highest in women and middle-aged people (40-59 years). The female predominance was lost in incident AQP4-IgG-seronegative children and AQP4-IgG-positive elder people. MOG-IgG and double-seronegativity contributed similarly but did not influence the long-term outcome.

Conclusion: The new criteria increase the estimates, but NMOSD remains as a rare disease. The differences in age- and sex-specific estimates highlight the importance of the serologic classification.
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http://dx.doi.org/10.1177/1352458517735191DOI Listing
December 2018

Anti-inflammatory disease-modifying treatment and short-term disability progression in SPMS.

Neurology 2017 Sep 9;89(10):1050-1059. Epub 2017 Aug 9.

Objective: To investigate the effect of disease-modifying treatment on short-term disability outcomes in secondary progressive multiple sclerosis (SPMS).

Methods: Using MSBase, an international cohort study, we previously validated a highly accurate definition of SPMS. Here, we identified patients in MSBase who were either untreated or treated with a disease-modifying drug when meeting this definition. Propensity score matching was used to select subpopulations with comparable baseline characteristics. Disability outcomes were compared in paired, pairwise-censored analyses adjusted for treatment persistence, visit density, and relapse rates.

Results: Of the 2,381 included patients, 1,378 patients were matchable (treated n = 689, untreated n = 689). Median pairwise-censored follow-up was 2.1 years (quartiles 1.2-3.8 years). No difference in the risk of 6-month sustained disability progression was observed between the groups (hazard ratio [HR] 0.9, 95% confidence interval [CI] 0.7-1.1, = 0.27). We also did not find differences in any of the secondary endpoints: risk of reaching Expanded Disability Status Scale (EDSS) score ≥7 (HR 0.6, 95% CI 0.4-1.1, = 0.10), sustained disability reduction (HR 1.0, 95% CI 0.8-1.3, = 0.79), or change in disability burden (area under the EDSS-time curve, β = -0.05, = 0.09). Secondary and sensitivity analyses confirmed the results.

Conclusions: Our pooled analysis of the currently available disease-modifying agents used after conversion to SPMS suggests that, on average, these therapies have no substantial effect on relapse-unrelated disability outcomes measured by the EDSS up to 4 years.

Classification Of Evidence: This study provides Class IV evidence that for patients with SPMS, disease-modifying treatment has no beneficial effect on short-term disability progression.
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http://dx.doi.org/10.1212/WNL.0000000000004330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589791PMC
September 2017

Monitoring CD49d Receptor Occupancy: A Method to Optimize and Personalize Natalizumab Therapy in Multiple Sclerosis Patients.

Cytometry B Clin Cytom 2018 03 17;94(2):327-333. Epub 2017 Apr 17.

Division of Immunology, Germans Trias i Pujol University Hospital and Research Institute, Campus Can Ruti, Badalona, Spain.

Background: In natalizumab-treated relapsing-remitting MS (RRMS) patients, various extended interval dosing strategies are under evaluation to minimize severe treatment-associated side effects, mainly progressive multifocal leukoencephalopathy development. Up to now, it has not been presented any approach, even in form of assay design, to determine the optimal percentage of CD49d receptor occupancy (RO) associated with a favorable clinical, radiological, and immunological response.

Methods: A multiparametric quantitative flow cytometry method was settled to measure CD49d RO on peripheral blood lymphocytes. The analytical protocol was tested in a 6-month follow-up from 19 RRMS patients treated with the natalizumab standard dosing of every 4 weeks or an extended-interval dosing of every 6 weeks.

Results: Extended natalizumab dose schedule promoted an increase of CD49d molecules per cell surface and a reduction of CD49d RO levels. The reduction observed on CD49d RO was not only depending on dose schedule but also on individual parameters such as body mass. Interestingly, individual clinical outcome was apparently the same between the different dose schedules or even better with the extended interval dosing.

Conclusions: Following up CD49d RO levels with a well-regulated monitoring work scheme is crucial to further identify over-/under-treated patients and to define a safe, personalized natalizumab regimen. © 2017 International Clinical Cytometry Society.
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http://dx.doi.org/10.1002/cyto.b.21527DOI Listing
March 2018

Defining secondary progressive multiple sclerosis.

Brain 2016 09 7;139(Pt 9):2395-405. Epub 2016 Jul 7.

1 Department of Medicine, University of Melbourne, Melbourne, Australia 2 Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia.

A number of studies have been conducted with the onset of secondary progressive multiple sclerosis as an inclusion criterion or an outcome of interest. However, a standardized objective definition of secondary progressive multiple sclerosis has been lacking. The aim of this work was to evaluate the accuracy and feasibility of an objective definition for secondary progressive multiple sclerosis, to enable comparability of future research studies. Using MSBase, a large, prospectively acquired, global cohort study, we analysed the accuracy of 576 data-derived onset definitions for secondary progressive multiple sclerosis and first compared these to a consensus opinion of three neurologists. All definitions were then evaluated against 5-year disease outcomes post-assignment of secondary progressive multiple sclerosis: sustained disability, subsequent sustained progression, positive disability trajectory, and accumulation of severe disability. The five best performing definitions were further investigated for their timeliness and overall disability burden. A total of 17 356 patients were analysed. The best definition included a 3-strata progression magnitude in the absence of a relapse, confirmed after 3 months within the leading Functional System and required an Expanded Disability Status Scale step ≥4 and pyramidal score ≥2. It reached an accuracy of 87% compared to the consensus diagnosis. Seventy-eight per cent of the identified patients showed a positive disability trajectory and 70% reached significant disability after 5 years. The time until half of all patients were diagnosed was 32.6 years (95% confidence interval 32-33.6) after disease onset compared with the physicians' diagnosis at 36 (35-39) years. The identified patients experienced a greater disease burden [median annualized area under the disability-time curve 4.7 (quartiles 3.6, 6.0)] versus non-progressive patients [1.8 (1.2, 1.9)]. This objective definition of secondary progressive multiple sclerosis based on the Expanded Disability Status Scale and information about preceding relapses provides a tool for a reproducible, accurate and timely diagnosis that requires a very short confirmation period. If applied broadly, the definition has the potential to strengthen the design and improve comparability of clinical trials and observational studies in secondary progressive multiple sclerosis.
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http://dx.doi.org/10.1093/brain/aww173DOI Listing
September 2016

Cryopreserved vitamin D3-tolerogenic dendritic cells pulsed with autoantigens as a potential therapy for multiple sclerosis patients.

J Neuroinflammation 2016 05 20;13(1):113. Epub 2016 May 20.

Division of Immunology, Germans Trias i Pujol University Hospital and Research Institute, Campus Can Ruti, Badalona, Spain.

Background: Tolerogenic dendritic cells (tolDC) have been postulated as a potent immunoregulatory therapy for autoimmune diseases such as multiple sclerosis (MS). In a previous study, we demonstrated that the administration of antigen-specific vitamin D3 (vitD3) tolDC in mice showing clinical signs of experimental autoimmune encephalomyelitis (EAE; the animal model of MS) resulted in abrogation of disease progression. With the purpose to translate this beneficial therapy to the clinics, we have investigated the effectivity of vitD3-frozen antigen-specific tolDC pulsed with myelin oligodendrocyte glycoprotein 40-55 peptide (f-tolDC-MOG) since it would reduce the cost, functional variability and number of leukapheresis to perform to the patients.

Methods: Mice showing EAE clinical signs were treated with repetitive doses of f-tolDC-MOG. Tolerogenic mechanisms induced by the therapy were analysed by flow cytometry and T cell proliferation assays.

Results: Treatment with f-tolDC-MOG was effective in ameliorating clinical signs of mice with EAE, inhibiting antigen-specific reactivity and inducing Treg. In addition, the long-term treatment was well tolerated and leading to a prolonged maintenance of tolerogenicity mediated by induction of Breg, reduction of NK cells and activation of immunoregulatory NKT cells.

Conclusions: The outcomes of this study show that the use of antigen-specific f-tolDC promotes multiple and potent tolerogenic mechanisms. Moreover, these cells can be kept frozen maintaining their tolerogenic properties, which is a relevant step for their translation to the clinic. Altogether, vitD3 f-tolDC-MOG is a potential strategy to arrest the autoimmune destruction in MS patients.
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http://dx.doi.org/10.1186/s12974-016-0584-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874005PMC
May 2016

Neuromyelitis optica spectrum disorders: Comparison according to the phenotype and serostatus.

Neurol Neuroimmunol Neuroinflamm 2016 Jun 14;3(3):e225. Epub 2016 Apr 14.

Authors' affiliations are listed at the end of the article.

Objective: To (1) determine the value of the recently proposed criteria of neuromyelitis optica (NMO) spectrum disorder (NMOSD) that unify patients with NMO and those with limited forms (NMO/LF) with aquaporin-4 immunoglobulin G (AQP4-IgG) antibodies; and (2) investigate the clinical significance of the serologic status in patients with NMO.

Methods: This was a retrospective, multicenter study of 181 patients fulfilling the 2006 NMO criteria (n = 127) or NMO/LF criteria with AQP4-IgG (n = 54). AQP4-IgG and myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG) antibodies were tested using cell-based assays.

Results: Patients were mainly white (86%) and female (ratio 6.5:1) with median age at onset 39 years (range 10-77). Compared to patients with NMO and AQP4-IgG (n = 94), those with NMO/LF presented more often with longitudinally extensive transverse myelitis (LETM) (p < 0.001), and had lower relapse rates (p = 0.015), but similar disability outcomes. Nonwhite ethnicity and optic neuritis presentation doubled the risk for developing NMO compared with white race (p = 0.008) or LETM presentation (p = 0.008). Nonwhite race (hazard ratio [HR] 4.3, 95% confidence interval [CI] 1.4-13.6) and older age at onset were associated with worse outcome (for every 10-year increase, HR 1.7, 95% CI 1.3-2.2). Patients with NMO and MOG-IgG (n = 9) had lower female:male ratio (0.8:1) and better disability outcome than AQP4-IgG-seropositive or double-seronegative patients (p < 0.001).

Conclusions: In patients with AQP4-IgG, the similar outcomes regardless of the clinical phenotype support the unified term NMOSD; nonwhite ethnicity and older age at onset are associated with worse outcome. Double-seronegative and AQP4-IgG-seropositive NMO have a similar clinical outcome. The better prognosis of patients with MOG-IgG and NMO suggests that phenotypic and serologic classification is useful.
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http://dx.doi.org/10.1212/NXI.0000000000000225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4841645PMC
June 2016

Baseline Differences in Minor Lymphocyte Subpopulations may Predict Response to Fingolimod in Relapsing-Remitting Multiple Sclerosis Patients.

CNS Neurosci Ther 2016 07 15;22(7):584-92. Epub 2016 Apr 15.

Immunology Division, Germans Trias i Pujol University Hospital and Research Institute, Badalona, Barcelona, Spain.

Aims: Fingolimod, oral treatment for relapsing-remitting multiple sclerosis (RRMS), is an agonist of sphingosine and its metabolite S1P that binds their receptors, blocking the egress of lymphocytes from lymph nodes. The aim of this study was immunomonitoring of minor peripheral lymphocyte subpopulations in RRMS patients under treatment with fingolimod and correlation with treatment response.

Methods: Prospective study. T- and B-cell subpopulations were analyzed using multiparametric flow cytometry in peripheral blood from 14 RRMS patients under treatment with fingolimod at baseline, +1, +3, +6, +9, and +12 months of follow-up. Response to therapy was assessed at month +12.

Results: Most changes in minor lymphocyte subpopulations occurred in the first month of treatment and were maintained until the end of follow-up. The basal percentages of recent thymic emigrants (RTEs) and transitional B cells were lower in responder patients than in nonresponders. After 1 month of follow-up, the percentages of late effector memory CD4(+) T cells in peripheral blood were higher in responder patients.

Conclusion: If confirmed in a bigger cohort of patients, analysis of percentages of minor lymphocyte subpopulations in peripheral blood of patients with RRMS prior and after +1 month of treatment might predict clinical response to fingolimod.
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http://dx.doi.org/10.1111/cns.12548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492868PMC
July 2016

Multiparametric flow cytometric analysis of whole blood reveals changes in minor lymphocyte subpopulations of multiple sclerosis patients.

Autoimmunity 2016 06 1;49(4):219-28. Epub 2016 Feb 1.

a Immunology Division, Germans Trias i Pujol University Hospital and Research Institute (IGTP) , Campus Can Ruti , Badalona , Barcelona .

Objective: The objective of this study is to characterise the functionally relevant minor lymphocyte subpopulations in whole blood of multiple sclerosis (MS) patients and their potential utility as biomarkers for treatment follow up.

Material And Methods: Peripheral blood from 40 healthy donors (HD) and 66 MS patients [23 relapsing-remitting (RRMS) without treatment, 27 RRMS undergoing treatment (16 IFN-β, 11 natalizumab), and 16 progressive forms (eight secondary progressive and eight primary progressive)] was analysed by multiparametric flow cytometry.

Results: Untreated MS patients showed a decrease in early effector memory (CD45RA(-)CCR7(-)CD27(+)) CD4(+) and CD8(+) T cells and an increase in Th17 lymphocytes in peripheral blood compared with HD. Regarding the effect of treatment, whereas no differences in relative percentages of cellular subpopulations were observed in patients under IFN-β treatment, those under treatment with natalizumab had an increased percentage of early effector memory CD4(+) (CD45RA(-)CCR7(-)CD27(+)), central memory CD8(+) (CD45RA(-)CCR7(+)CD27(+)) T cells, recent thymic emigrants (CD4(+) CD45RA(+)CCR7(+)CD27(+)CD31(+)PTK7(+)) and transitional B cells (CD19(+)CD27(-)CD24(hi)CD38(hi)).

Conclusions: Multiparametric flow cytometry analysis of whole blood is a robust, reproducible, and sensitive technology to monitor the effect of MS treatments even in minor lymphocyte subpopulations that might represent useful biomarkers of treatment response.
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http://dx.doi.org/10.3109/08916934.2016.1138271DOI Listing
June 2016

Baseline clinical status as a predictor of methylprednisolone response in multiple sclerosis relapses.

Mult Scler 2016 Jan 25;22(1):117-21. Epub 2015 Jun 25.

Hospital Germans Trias i Pujol, Badalona, Spain.

Background: To date, there are no available factors to predict the outcome after multiple sclerosis relapse.

Aim: To investigate factors that may be useful for predicting response to methylprednisolone treatment, following a relapse of multiple sclerosis (MS).

Methods: The study included 48 MS patients enrolled in a double-blind multicenter trial to receive intravenous versus oral high-dose methylprednisolone treatment. Associations were sought between the disability status prior to relapse and the relapse severity, determined by changes in the Expanded Disability Status Scale (EDSS) score, as well as the improvements after treatment. We also analyzed the relationships between the number of magnetic resonance imaging (MRI) gadolinium-enhancing lesions (Gd+) and improvement.

Results: A higher EDSS score before relapse was associated with more severe relapses (p = 0.04) and less marked improvement (odds ratio (OR) 1.8; 95% CI (1.2-2.2); p = 0.05) after methylprednisolone treatment. Relapse severity (p = 0.29) and the number of Gd+ lesions at relapse (p = 0.41) were not related with improvement.

Conclusions: Clinical baseline status prior to MS relapse is a predictor of response to methylprednisolone treatment.
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http://dx.doi.org/10.1177/1352458515590648DOI Listing
January 2016

Progressive multifocal leukoencephalopathy associated to natalizumab extended dosing regimen.

Neurodegener Dis Manag 2015 Oct 30;5(5):399-402. Epub 2015 Oct 30.

Department of Neurosciences, Multiple Sclerosis Unit, Germans Trias i Pujol Hospital. C/Canyet s/n 08916, Badalona, Spain.

A risk for developing progressive multifocal leukoencephalopathy is a major barrier to natalizumab use. Extended dosing intervals have been proposed as a way to maintain therapeutic efficacy and reduce progressive multifocal leukoencephalopathy incidence. This is the first reported case of progressive multifocal leukoencephalopathy in a patient using an extended dosing regimen (300 mg/6 weeks). A close clinical and imaging monitoring allowed early detection, which is a major prognostic factor. A favorable outcome was seen with a therapy comprising plasma exchange therapy, mirtazapine, mefloquine and cidofovir. Further studies will be needed to assess the potential role of extended dosing intervals to improve prognosis in patients receiving natalizumab and also to measure its impact clinically and/or radiologically.
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http://dx.doi.org/10.2217/nmt.15.42DOI Listing
October 2015

Beneficial effect of tolerogenic dendritic cells pulsed with MOG autoantigen in experimental autoimmune encephalomyelitis.

CNS Neurosci Ther 2015 Mar 18;21(3):222-30. Epub 2014 Nov 18.

Division of Immunology, Germans Trias i Pujol University Hospital and Research Institute, Campus Can Ruti, Badalona, Spain; Department of Cellular Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.

Background: Treatment with tolerogenic dendritic cells (TolDC) is a promising, cell-based strategy to regulate autoimmune diseases such as multiple sclerosis (MS) in an antigen-specific way. This technique involves the use of TolDC from MS patients cultured in the presence of vitamin D(3) (VitD3) and pulsed with myelin peptides to induce a stable hyporesponsiveness in myelin-specific autologous T cells.

Aim: The purpose of this study was to analyze the in vivo effect of VitD3-TolDC treatment on experimental autoimmune encephalomyelitis, an animal model of MS.

Methods: Bone marrow-derived TolDC cultured in the presence of VitD3 and pulsed with peptide 40-55 of the myelin oligodendrocyte glycoprotein (MOG(40-55)) were administrated preventively, preclinically, and therapeutically to EAE-induced mice.

Results: We found that VitD3-TolDC-MOG treatment showed a beneficial effect, not only decreasing the incidence of the disease but also reducing the severity of the clinical signs mediated by induction of regulatory T cells (Treg), as well as IL-10 production and reduction of Ag-specific lymphoproliferation. Our results support VitD3-TolDC-peptide(s) treatment as a potential strategy to restore tolerance in autoimmune diseases such as MS.
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http://dx.doi.org/10.1111/cns.12342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6495243PMC
March 2015

[Encephalopathy and neuromyelitis optica: the importance of recognising atypical symptoms].

Rev Neurol 2014 Jan;58(1):20-4

Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Espana.

Introduction: Neuromyelitis optica (NMO), or Devic's disease, is an autoimmune, inflammatory and demyelinating disease of the central nervous system which mainly and characteristically involves the optic nerve and the spinal cord. Anti-aquaporin-4 (AQ-4) antibodies are a specific biomarker of the entity and, since their discovery, both the number of symptoms and the radiological data about the disease have progressively increased, and the concept of clinical spectrum of NMO has been defined.

Case Report: A 66-year-old female diagnosed with NMO after suffering attacks of optic neuritis and recurrent myelitis, and showing positive for AQ-4 antibodies. The patient presented a diminished level of consciousness, and magnetic resonance imaging of the head revealed a number of lesions in the white matter, without contrast enhancement, which resolved without treatment. One month later, her general state had declined and was accompanied by symptoms of confusion and blindness. A magnetic resonance imaging scan showed new lesions in the white matter and an increase in the size of those already present. The patient was diagnosed as suffering from encephalopathy within the context of NMO and she was treated with intravenous immunoglobulins and corticoids, which resulted in a clinical and radiological improvement.

Conclusions: Since the discovery of AQ-4 antibodies, there has been an increase in the number of clinical and radiological manifestations of NMO beyond involvement of the optic nerve and the spinal cord, including manifestations in the brain. It is important to recognise them in order to make an early diagnosis, to avoid unnecessary complementary tests and to establish the most suitable treatment.
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January 2014

[Lesion of the trigeminal nucleus caused by herpes simplex virus].

Rev Neurol 2013 Dec;57(11):526-7

Hospital Universitari Germans Trias i Pujol, 08916 Badalona, Espana.

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December 2013

Regulatory role of vitamin D in T-cell reactivity against myelin peptides in relapsing-remitting multiple sclerosis patients.

BMC Neurol 2012 Sep 24;12:103. Epub 2012 Sep 24.

Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Carretera del Canyet s/n, Badalona, Barcelona, 08916, Spain.

Background: Low levels of plasma 25-hydroxyvitaminD (25(OH)D) are associated with a higher incidence of multiple sclerosis (MS) due to the immune suppressive properties of vitamin D.The aim of this study was to determine the correlation between plasma 25(OH)D concentrations and clinical and immunological variables in a cohort of multiple sclerosis patients.

Methods: Plasma 25(OH)D concentrations were evaluated in summer and winter in 15 primary progressive MS (PPMS) patients, 40 relapsing- remitting MS (RRMS) patients and 40 controls (HC). Protocol variables included demographic and clinical data, radiological findings and immunological variables (oligoclonal bands, HLADR15 and T-lymphocyte proliferation to a definite mix of 7 myelin peptides).

Results: During the winter, plasma concentrations were significantly lower in RRMS patients compared to HC, whereas no differences were found in summer. No relationships were found between plasma 25(OH)D concentrations and clinical or radiological variables. RRMS patients with a positive T-cell proliferation to a mix of myelin peptides (n = 31) had lower 25(OH)D concentrations.

Conclusions: 25(OH)D is an immunomodulatory molecule that might have a regulatory role in T-cell proliferation to myelin peptides in RRMS patients.
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http://dx.doi.org/10.1186/1471-2377-12-103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3488583PMC
September 2012