J Río

University Hospital Vall d'Hebron, Barcino, Catalonia, Spain

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Publications (139)606.5 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Several autoimmune diseases (ADs) can mimic multiple sclerosis (MS). For this reason, testing for auto-antibodies (auto-Abs) is often included in the diagnostic work-up of patients with a clinically isolated syndrome (CIS). The purpose was to study how useful it was to systematically determine antinuclear-antibodies, anti-SSA and anti-SSB in a non-selected cohort of CIS patients, regarding the identification of other ADs that could represent an alternative diagnosis. From a prospective CIS cohort, we selected 772 patients in which auto-Ab levels were tested within the first year from CIS. Baseline characteristics of auto-Ab positive and negative patients were compared. A retrospective revision of clinical records was then performed in the auto-Ab positive patients to identify those who developed ADs during follow-up. One or more auto-Ab were present in 29.4% of patients. Only 1.8% of patients developed other ADs during a mean follow-up of 6.6 years. In none of these cases the concurrent AD was considered the cause of the CIS. In all cases the diagnosis of the AD resulted from the development of signs and/or symptoms suggestive of each disease. Antinuclear-antibodies, anti-SSA and anti-SSB should not be routinely determined in CIS patients but only in those presenting symptoms suggestive of other ADs. © The Author(s), 2015.
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    ABSTRACT: INTRODUCTION. Natalizumab is a drug used in multiple sclerosis (MS) and its main side effect is the development of progressive multifocal leukoencephalopathy (PML). Since this is potentially fatal or disabling, treatment must be stopped immediately if it is suspected, taking into account the possible later development of immune reconstitution syndrome or renewed exacerbation of MS. CASE REPORT. We report a case of initially asymptomatic PML within the context of treatment with natalizumab in a female patient with MS. High antibody titers to the John Cunningham virus (JCV) and over two years' treatment were established as risk factors. The polymerase chain reaction for the JCV in cerebrospinal fluid was negative in two determinations. The interval between the radiological diagnosis and the onset of the clinical features was two months. During the course of the disease, the patient developed immune reconstitution inflammatory syndrome and relapses, or renewed exacerbation, of her MS. She responded well after beginning treatment with fingolimod, once the PML had become stabilised. CONCLUSIONS. This case indicates the importance of close clinico-radiological monitoring in patients with MS treated with natalizumab, especially when they present risk factors for the development of PML, as well as its potential incidence on survival and final functional status.
  • Jordi Río
    Multiple Sclerosis 01/2015; DOI:10.1177/1352458514565415 · 4.86 Impact Factor
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    ABSTRACT: Evidence exists for a potential modulation of inflammasome activity by interferon beta. Here, we investigated the roles of inflammasomes [absent in melanoma 2 (AIM2); NLR family, CARD domain containing 4 (NLRC4); NLR family, pyrin domain containing 1 and 3 (NLRP1 and NLRP3)] and related cytokines (IL1B, IL10, IL18) in the response to interferon beta in patients with relapsing-remitting multiple sclerosis. Ninety-seven patients treated with interferon beta were classified into responders and non-responders according to clinical criteria after 24 months and clinical-radiological criteria after 12 months of treatment. Messenger RNA expression levels of inflammasomes and cytokines were determined by real-time polymerase chain reaction in peripheral blood mononuclear cells collected before treatment with interferon beta. In a subgroup of patients, NLRP3 and IL1B expression was also determined after 3 months (n = 32) and 12 months (n = 20) of interferon beta treatment. A polymorphism located in the NLRP3 gene, rs35829419, was genotyped in 789 multiple sclerosis patients treated with interferon beta. Baseline mRNA expression levels for NLRP3 and IL1B were increased in peripheral blood mononuclear cells from non-responders compared to responders classified according to clinical criteria after 24 months (P = 0.02 and P = 0.001, respectively). No significant differences were observed for other inflammasomes and related cytokines. Differences in NLRP3 and IL1B expression remained significant following a clinical-radiological classification after 12 months (P = 0.007 and P = 0.02, respectively). After treatment with interferon beta, NLRP3 and IL1B expression was increased in responders but unchanged in non-responders. A trend for association was observed between rs35829419 and interferon beta response (pM-H = 0.08). These results point to a role of the NLRP3 inflammasome and its related cytokine IL1B in the response to interferon beta in patients with relapsing-remitting multiple sclerosis. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Brain 01/2015; DOI:10.1093/brain/awu388 · 10.23 Impact Factor
  • Jordi Río, Xavier Montalbán
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    ABSTRACT: Multiple sclerosis is a multifocal demyelinating disease leading to progressive neurodegeneration caused by an autoimmune response in genetically predisposed individuals. In the last few years, the knowledge and management of this disease has been revolutionized by a series of findings. The present article reviews pathological features of the disease, in which cortical involvement is increasingly implicated, and aspects related to novel pathogenic mechanisms, such as the role of the microbiota in the genesis of multiple sclerosis, as well as recent contributions from the fields of epidemiology and genetics. Also reviewed are the latest diagnostic criteria, which currently allow a much earlier diagnosis, with clear therapeutic implications. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.
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    ABSTRACT: We aimed to single out multiple sclerosis (MS) cases with poor outcome after natalizumab withdrawal and to identify predictive variables. We ascertained 47 withdrawals, and compared their pre- and post-natalizumab periods. We objectively defined significant clinical worsening after natalizumab withdrawal as a 2-step increase in Expanded Disability Status Scale (EDSS). We performed regression models. As a group, post-natalizumab annualized relapse rate (ARR) was lower in the post-natalizumab period, and there were no differences in the mean number of gadolinium (Gd)-enhancing lesions between pre- and post-natalizumab magnetic resonance imaging (MRI). Corticosteroid treatment did not change the outcomes. Eight patients (19%) presented significant clinical worsening after natalizumab withdrawal, which was predicted by a higher baseline EDSS and a 1-step EDSS increase while on natalizumab.
    Multiple Sclerosis 11/2014; DOI:10.1177/1352458514549401 · 4.86 Impact Factor
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    ABSTRACT: A pseudoatrophy effect has been held responsible for the lack of net impact of natalizumab on brain volume outcomes in 2-year trials, but no data are available beyond 24 months.
    Multiple Sclerosis 11/2014; DOI:10.1177/1352458514556300 · 4.86 Impact Factor
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    ABSTRACT: Apoptosis is a major mechanism regulating immune tolerance by the elimination of autoreactive T lymphocytes. A failure of activation induced cell-death (AICD) has been described in T lymphocytes from patients with multiple sclerosis (MS). The aim of this study was to evaluate AICD in T lymphocytes from patients with MS and healthy controls, and to explore the molecular mechanisms underlying the deregulation observed in apoptosis induction. PHA-induced AICD was reduced in T lymphocytes from patients with relapsing-remitting MS compared with controls. This finding was associated with a diminished expression of Fas and a failure in caspase 3 activation.
    Journal of neuroimmunology 07/2014; DOI:10.1016/j.jneuroim.2014.04.007 · 2.79 Impact Factor
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    ABSTRACT: Recombinant interferon β (IFNβ) is a first-line therapy for relapsing-remitting multiple sclerosis (MS), with a proven effect on the inflammatory activity. Neutralising antibodies against IFNβ (NAbs) promote a loss of IFNβ bioactivity in a titre-dependent way and their development was associated with certain human leucocyte antigen (HLA) alleles. We investigated the contribution conferred by HLA alleles on the development of NAbs in independent cohorts of Southern Europe. Serum NAbs from 610 MS patients with HLA-genotype data were evaluated by cytopathic effect assay: negative tests included at least one negative result (NAb titres<20 NU/mL) after 1 year treatment; NAb-titres ≥20 NU/mL were positive tests and NAb titres ≥150 NU/mL in any test were classified as high-titre positives. The combined presence of DRB1*07/DQA1*02 with A*26 or B*14 was found in 20% of patients with NAbs at high titres, but only in 5.4% of NAb-negative patients (p=0.00052, OR (95% CI) 4.34 (1.85 to 10.13)). The DRB1*04:01 allele was also more frequently carried by patients with high titres of NAbs (10% vs 4.5%; p=0.046, OR (95% CI) 2.38 (0.93 to 5.92)). The alleles carried at a significantly lower frequency in patients with high persistent NAbs corresponded to the A*11 allele (3.3% vs 13.8%; p=0.023, OR (95% CI) 0.22 (0.02 to 0.87)), as well as the DRB1*03/DQA1*05/DQB1*02 haplotype (16.3% vs 26.8%; p=0.02, OR (95% CI) 0.53 (0.27 to 1.03)) and the DRB1*13/DQA1*01:03/DQB1*06:03 haplotype (2.5% vs 9.1%; p=0.045, OR (95% CI) 0.25 (0.03 to 1.02)). 50% of the studied MS patients carried some of the five independently associated HLA allele/allele combinations described in this work. This relevant percentage of patients could benefit a therapeutic decision.
    Journal of Medical Genetics 04/2014; 51(6). DOI:10.1136/jmedgenet-2014-102348 · 5.64 Impact Factor
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    ABSTRACT: In patients with relapsing-remitting multiple sclerosis (RRMS), a scoring system based on new magnetic resonance imaging (MRI) active lesions, relapses and sustained disability progression after a 1-year treatment with IFNβ predicted patient disability progression over time; however, this score had not been tested in patients receiving glatiramer acetate (GA). The objective of this study was to evaluate whether this previous scoring system can also be applied to patients treated with GA. This was a prospective, longitudinal study of 151 RRMS patients treated with GA. Their scores were constructed, based on the clinical and MRI activity after 1 year of therapy. Regression analysis was performed, in order to identify the response variables. The total possible score range was 0-3. Patients with a score of ≥ 2 and those with clinical activity (with or without MRI activity) during their first year of treatment were at increased risk of continuing with relapses and/or sustained disability in the next 2 years (odds ratio (OR): 38.8; p < 0.0001 and OR: 7.8; p < 0.009, respectively). In RRMS patients treated with GA, a combination of clinical activity measures may have prognostic value for identifying patients with disease activity in the next 2 years of therapy.
    Multiple Sclerosis 03/2014; 20(12). DOI:10.1177/1352458514527863 · 4.86 Impact Factor
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    ABSTRACT: Abstract Inducible heat shock protein (HSP)70 (HSP70-1A and HSP70-1B proteins) is a chaperone responsible for assisting proper protein folding. Following stress conditions, HSP70 is highly up-regulated to mediate cytoprotective functions. In addition, HSP70 is able to trigger innate and adaptive immune responses that promote the immune recognition of antigens and to act as a cytokine when it is released. The data in the literature are controversial with regard to expression studies in peripheral blood mononuclear cells (PBMCs). In the present study, we aimed to examine if alterations of HSP70-1A/B expression are involved in the autoimmune pathogenesis of multiple sclerosis (MS). We determined both mRNA and protein expression in PBMCs of MS patients and healthy donors (HDs). We found a baseline increased expression of the HSPA1A gene in PBMCs from MS patients compared with HDs. Gene expression findings were associated with an increased protein expression of HSP70-1A/B in T lymphocytes (CD4+ and CD8+) and monocytes from MS patients under basal conditions that may reflect the immunological activation occurring in MS patients. We also provided evidence that heat shock (HS) stimulus induced HSP70-1A/B protein expression in HDs and MS patients, and that HS-induced HSP70-1A/B protein expression in monocytes correlated with the number of T2 lesions at baseline in MS patients. However, after lipopolysaccharide inflammatory stimulus, monocytes from MS patients failed to induce HSP70-1A/B protein expression. Our data hint at altered immune responses in MS and may indicate either a state of chronic stress or increased vulnerability to physiological immune responses in MS patients.
    Autoimmunity 12/2013; DOI:10.3109/08916934.2013.866104 · 2.75 Impact Factor
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    ABSTRACT: We aimed to investigate the ability of natalizumab (NTZ)-treated patients to assume treatment-associated risks and the factors involved in such risk acceptance. From a total of 185 patients, 114 patients on NTZ as of July 2011 carried out a comprehensive survey. We obtained disease severity perception scores, personality traits' scores, and risk-acceptance scores (RAS) so that higher RAS indicated higher risk acceptance. We recorded JC virus status (JCV+/-), prior immunosuppression, NTZ treatment duration, and clinical characteristics. NTZ patients were split into subgroups (A-E), depending on their individual PML risk. Some 22 MS patients on first-line drugs (DMD) acted as controls. No differences between treatment groups were observed in disease severity perception and personality traits. RAS were higher in NTZ than in DMD patients (p<0.01). Perception of the own disease as a more severe condition tended to predict higher RAS (p=0.07). Higher neuroticism scores predicted higher RAS in the NTZ group as a whole (p=0.04), and in high PML-risk subgroups (A-B) (p=0.02). In low PML-risk subgroups (C-E), higher RAS were associated with a JCV+ status (p=0.01). Neither disability scores nor pre-treatment relapse rate predicted RAS in either group. Risk acceptance is a multifactorial phenomenon, which might be partly explained by an adaptive process, in light of the higher risk acceptance amongst NTZ-treated patients and, especially, amongst those who are JCV seropositive but still have low PML risk, but which seems also intimately related to personality traits.
    PLoS ONE 12/2013; 8(12):e82796. DOI:10.1371/journal.pone.0082796 · 3.53 Impact Factor
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    ABSTRACT: Background Neutralising antibodies (NABs)against interferon beta have been describedin one third of patients with multiple sclerosistreated with interferon beta. We haveanalysed the frequency of NABs and theirclinical consequences. Patients and methods We have studied 68patients. NABs were determined by proteinA Myxovirus assay. Results Positive NABs were detected in 13%of the patients after 2 years of treatment. Conclusions It does not seem to exist a relationshipbetween presence of NABs and apoor evolution of the disease in our patientswith multiple sclerosis treated with beta interferon.
    Medicina Clínica 08/2013; 114(5):169–170. DOI:10.1016/S0025-7753(00)71232-2 · 1.25 Impact Factor
  • Medicina Clínica 08/2013; 114(1):38. DOI:10.1016/S0025-7753(00)71181-X · 1.25 Impact Factor
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    ABSTRACT: BACKGROUND AND PURPOSE: Ubiquitin specific peptidase 18 (USP18) is a deubiquitinating enzyme that functions as a negative regulator of the type I interferon (IFN) signalling pathway and is specifically induced by type I IFNs. In the present study, previous observations by our group were expanded suggesting an implication of USP18 in multiple sclerosis (MS) based on the finding of a deficient expression of the gene in peripheral blood mononuclear cells from MS patients compared with healthy controls. METHODS: Two polymorphisms, rs2542109 (intronic) and rs9618216 (promoter), were genotyped in a cohort of 691 relapse-onset MS patients and 1028 healthy controls and in 225 MS patients treated with IFNβ and classified into responders and non-responders after 2 years of treatment according to clinical criteria. Correlations between genotypes and expression levels for USP18 and its target ISG15 were performed by real-time polymerase chain reaction. RESULTS: Two USP18 haplotypes were significantly associated with MS, TG and CG. Additional experiments revealed that CG carriers were characterized by lower USP18 gene expression levels in peripheral blood mononuclear cells and higher clinical disease activity. Finally, AA homozygosis for the intronic polymorphism rs2542109 was associated with the responder phenotype; however, USP18 expression levels induced by IFNβ did not differ amongst MS patients carrying different rs2542109 genotypes. CONCLUSIONS: Altogether, these results point to a role of USP18 in MS pathogenesis and the therapeutic response to IFNβ.
    European Journal of Neurology 05/2013; 20(10). DOI:10.1111/ene.12193 · 3.85 Impact Factor
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    ABSTRACT: BACKGROUND: The impact of global and tissue-specific brain atrophy on conversion to multiple sclerosis (MS) after a clinically isolated syndrome (CIS) is not fully gauged. OBJECTIVES: We aimed to determine the magnitude and clinical relevance of brain volume dynamics in the first year after a CIS. METHODS: We assessed 176 patients with CIS within 3 months of onset, clinically and by conventional magnetic resonance imaging (MRI) scans, at baseline and 1 year after clinical onset. We determined the percentage of brain volume change (PBVC) and the brain parenchymal (BPF), grey matter (GMF) and white matter (WMF) fractions. RESULTS: The mean follow-up time was 53 months (SD = 16.8): 76 patients (43%) experienced a second attack, 32 (18%) fulfilled MRI-only 2005 McDonald criteria and 68 (39%) remained as CIS. Statistically significant decreases in the volume measures tested were observed in patients with a second attack, for BPF and PBVC; in both MS groups for GMF; whereas in all groups, the WMF was unchanged. Patients with a second attack had larger PBVC decreases (- 0.65% versus + 0.059%; p < 0.001). PBVC decreases below - 0.817% independently predicted shorter times to a second attack. CONCLUSIONS: Global brain and grey matter volume loss occurred within the first year after a CIS; brain volume loss predicted conversion to MS.
    Multiple Sclerosis 05/2013; 19(14). DOI:10.1177/1352458513488231 · 4.86 Impact Factor
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    ABSTRACT: A relatively large proportion of relapsing-remitting multiple sclerosis (RRMS) patients do not respond to interferon-beta (IFNb) treatment. In previous studies with peripheral blood mononuclear cells (PBMC), we identified a subgroup of IFNb non-responders that was characterized by a baseline over-expression of type I IFN inducible genes. Additional mechanistic experiments carried out in IFNb non-responders suggested a selective alteration of the type I IFN signaling pathway in the population of blood monocytes. Here, we aimed (i) to investigate whether the type I IFN signaling pathway is up-regulated in isolated monocytes from IFNb non-responders at baseline; and (ii) to search for additional biological pathways in this cell population that may be implicated in the response to IFNb treatment. Twenty RRMS patients classified according to their clinical response to IFNb treatment and 10 healthy controls were included in the study. Monocytes were purified from PBMC obtained before treatment by cell sorting and the gene expression profiling was determined with oligonucleotide microarrays. Purified monocytes from IFNb non-responders were characterized by an over-expression of type I IFN responsive genes, which confirms the type I IFN signature in monocytes suggested from previous studies. Other relevant signaling pathways that were up-regulated in IFNb non-responders were related with the mitochondrial function and processes such as protein synthesis and antigen presentation, and together with the type I IFN signaling pathway, may also be playing roles in the response to IFNb.
    PLoS ONE 04/2013; 8(4):e60994. DOI:10.1371/journal.pone.0060994 · 3.53 Impact Factor
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    ABSTRACT: We investigated cellular immune responses at baseline in peripheral blood mononuclear cells (PBMC) of patients with multiple sclerosis (MS) treated with interferon (IFN)-β and classified into responders and non-responders according to clinical response criteria. Levels for IFN-γ, interleukin (IL)-17A, IL-17F, IL-10 and IL-4 were determined in activated PBMC of 10 responders, 10 non-responders and 10 healthy controls by cytometric bead arrays. Cytokine levels in cell culture supernatants were similar between responders and non-responders, and comparable to those obtained in healthy controls. These findings do not support differential cellular immune responses in PBMC at baseline between IFN-β responders and non-responders.
    Clinical & Experimental Immunology 03/2013; 171(3):243-6. DOI:10.1111/cei.12016 · 3.28 Impact Factor
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    ABSTRACT: BACKGROUND: Investigation of atrophy data from a pivotal natalizumab trial has demonstrated an increased rate of volume loss, compared to placebo, after the first year of therapy. It was considered to be probably due to a pseudoatrophy effect. OBJECTIVE: To assess grey and white matter volume changes and their relation to global brain volume changes and to baseline inflammation, for patients under natalizumab therapy. METHODS: We selected 45 patients on natalizumab therapy for at least 24 months, with magnetic resonance imaging (MRI) scans at baseline, 12 and 24 months. We calculated the percentage brain volume change (PBVC) for the first and second year, using SIENA software. Grey and white matter fractions (GMF and WMF, respectively) for the first year were calculated with SPM5, using lesion masks. After quality checks, six patients were excluded. We studied the predictive variables of change in brain volumes. RESULTS: The PBVC decrease was faster during the first year (-1.10% ± 1.43%), as compared to the second (-0.51% ± 0.96%) (p = 0.037). These differences were more marked in patients with baseline gadolinium-enhancing lesions (p = 0.005). Mean GMF and WMF changes during the first year of treatment were +1.15% (n.s.) and -1.72% (p = 0.017), respectively. The presence of active lesions at baseline MRI predicted PBVC (p = 0.022) and WMF change (p = 0.026) during the first year of treatment, after adjusting for age and corticosteroid treatment. No predictors were found for GMF volume changes. CONCLUSION: Early brain volume loss during natalizumab therapy is mainly due to WMF volume loss and it is related to the inflammatory activity present at the onset of therapy. We found that the pseudoatrophy effect is mostly due to white matter volume changes.
    Multiple Sclerosis 01/2013; 19(9). DOI:10.1177/1352458512473190 · 4.86 Impact Factor
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    ABSTRACT: INTRODUCTION. Immunomodulator treatment modifies the course of the disease in patients with multiple sclerosis. The patient's adequate adherence with the treatment regimen is absolutely essential. AIMS. To determine the real adherence with first-line immunomodulator treatment and to try to find out what factors may influence adequate adherence with the treatment. PATIENTS AND METHODS. We conducted an observation-based, retrospective, longitudinal study of the patients being followed up by the Centre d'Esclerosi Multiple de Catalunya at the Hospital Universitari Vall d'Hebron that were given first-line immunomodulator treatment (interferons or glatiramer acetate) between 1st January 2010 and 30th September 2011. Adherence was measured using the medication possession ratio (MPR): patients with an MPR above or equal to 80% were considered to be compliers. RESULTS. We studied 975 patients. The mean time of exposure to immunomodulators over the collected period was 13.4 ± 7.1 years. Altogether 85.2% of patients complied with the immunomodulator treatment adequately. Of a total of 975 patients treated, 134 needed to change to a second drug and 12 patients had to go on to a third. Changing the medication improved adherence (p = 0.001). The annual rate of attacks was 0.23. Only the presence of attacks (p = 0.029) and the drug used (p = 0.044) had any influence on treatment adherence, on an individual basis. CONCLUSIONS. The percentage of patients with adequate treatment adherence in our centre is high. The rate of attacks and the drug used play a decisive role. Close monitoring and personalised counselling are required to maintain good therapeutic adherence.
    Revista de neurologia 01/2013; 56(1):8-12. · 0.93 Impact Factor

Publication Stats

3k Citations
606.50 Total Impact Points

Institutions

  • 1996–2015
    • University Hospital Vall d'Hebron
      • Department of Neurology
      Barcino, Catalonia, Spain
  • 2014
    • VHIR Vall d’Hebron Research Institute
      Barcino, Catalonia, Spain
  • 2013
    • Universidad de Las Palmas de Gran Canaria
      Las Palmas, Canary Islands, Spain
    • Institut Marqués, Spain, Barcelona
      Barcino, Catalonia, Spain
  • 2010–2013
    • Autonomous University of Barcelona
      • Department of Medicine
      Cerdanyola del Vallès, Catalonia, Spain
  • 1996–2011
    • University of Barcelona
      • Department of Statistics
      Barcino, Catalonia, Spain
  • 2006
    • Hospital Clinica Benidorm
      Benidorm, Valencia, Spain
  • 2004
    • University of Naples Federico II
      Napoli, Campania, Italy
  • 2000
    • Hospital de Barcelona. SCIAS
      Barcino, Catalonia, Spain