J Río

VHIR Vall d’Hebron Research Institute, Barcino, Catalonia, Spain

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Publications (134)557.84 Total impact

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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 (Houndmills, Basingstoke, England). 11/2014;
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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 (Houndmills, Basingstoke, England). 11/2014;
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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; · 5.70 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; · 4.47 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 01/2014; · 2.84 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; · 2.77 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.
  • Medicina Clínica. 08/2013; 114(1):38.
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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; · 4.16 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; · 4.47 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. · 3.41 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; · 4.47 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 01/2013; 8(12):e82796. · 3.53 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 01/2013; 8(4):e60994. · 3.53 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. · 1.18 Impact Factor
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    ABSTRACT: Type I interferons (IFNs) are known to enhance humoral immunity. Here, we investigated the prevalence and titer of anti-nuclear and anti-neuronal IgG autoantibodies in 71 relapsing-remitting MS patients classified based on their clinical response to IFNβ in paired sera obtained at baseline and after 12months of treatment. All samples were negative for antibodies against cytoplasmic rods/rings, synaptic proteins and paraneoplastic antibodies. Regarding anti-nuclear, anti-filament and anti-myelin antibodies, pre- and post-treatment prevalence and titers did not differ significantly between IFNβ responders and non-responders. Thus, pattern of anti-nuclear and anti-neuronal autoantibodies does not predict the response to IFNβ in MS patients.
    Journal of neuroimmunology 11/2012; · 2.84 Impact Factor
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    ABSTRACT: OBJECTIVE: The aim of this study is to report the clinical profile and outcome of longitudinally extensive transverse myelitis (LETM). METHODS: We prospectively studied adult patients who presented with LETM from January 2008 to December 2011. Information on demographic, clinical course, magnetic resonance imaging (MRI) and outcome was collected. HLA-DRB1 genotype was compared with those of 225 normal controls and patients with MS (228) and neuromyelitis optica (NMO) (22). RESULTS: In total, 23 patients (16 female) with a median age of 44.5 years (range: 20-77 years) were included. Most (74%) had moderate-severe disability at nadir (48% non-ambulatory), normal/non-multiple sclerosis (MS) brain MRI (96%) and a median MRI cord lesion of 5 vertebral segments (range: 3-19). Laboratory analysis showed cerebrospinal fluid pleocytosis (45%), NMO-IgG (9%), antinuclear antibodies (70%), and genotype HLA-DRB1*13 (57%). The frequency of DRB1*13 genotype was higher compared with controls (p=0.002), MS (p=0.001) and NMO (p= 0.003) patients. After a median follow-up of 32 months, one patient converted to MS, two had relapsing LETM with NMO-IgG, and 20 remained as idiopathic with recurrences in four (20%). Twelve (52%) patients recovered with minimal disability (Expanded Disability Status Scale (EDSS) <2.5) and three (13%) remained wheelchair dependent. Disability at nadir was associated with the final outcome and extension of the spinal cord lesion with risk of recurrence. Recurrence was not associated with worse outcome. CONCLUSIONS: Inflammatory LETM is mostly idiopathic with a good outcome. It includes a relatively homogenous group of patients with an overrepresentation of the HLA-DRB1*13 genotype. EDSS at nadir is a predictor of the final outcome and extension of the myelitis of the recurrence risk.
    Multiple Sclerosis 10/2012; · 4.47 Impact Factor
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    ABSTRACT: BACKGROUND: We employed clinical and magnetic resonance imaging (MRI) measures in combination, to assess patient responses to interferon in multiple sclerosis. OBJECTIVE: To optimize and validate a scoring system able to discriminate responses to interferon treatment in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: Our analysis included two large, independent datasets of RRMS patients who were treated with interferons that included 4-year follow-up data. The first dataset ("training set") comprised of 373 RRMS patients from a randomized clinical trial of subcutaneous interferon beta-1a. The second ("validation set") included an observational cohort of 222 RRMS patients treated with different interferons. The new scoring system, a modified version of that previously proposed by Rio et al., was first tested on the training set, then validated using the validation set. The association between disability progression and risk group, as defined by the score, was evaluated by Kaplan Meier survival curves and Cox regression, and quantified by hazard ratios (HRs). RESULTS: The score (0-3) was based on the number of new T2 lesions (>5) and clinical relapses (0,1 or 2) during the first year of therapy. The risk of disability progression increased with higher scores. In the validation set, patients with score of 0 showed a 3-year progression probability of 24%, while those with a score of 1 increased to 33% (HR = 1.56; p = 0.13), and those with score greater than or equal to 2 increased to 65% (HR = 4.60; p < 0.001). CONCLUSIONS: We report development of a simple, quantitative and complementary tool for predicting responses in interferon-treated patients that could help clinicians make treatment decisions.
    Multiple Sclerosis 09/2012; · 4.47 Impact Factor
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    ABSTRACT: Despite the availability of diagnostic criteria, an overlap between neuromyelitis optica (NMO) and multiple sclerosis (MS) exists, particularly in the early stage of the disease. To study the value of NMO-immunoglobulin G (IgG) determination in Caucasian patients with a first demyelinating episode who develop a relapsing form of optic neuritis or myelitis. This study was based on a prospectively acquired cohort of patients regarded as having a clinically isolated syndrome (CIS) at the time of presentation. From this cohort, 2 different groups were selected: group 1 (NMO phenotype), consisting of a first attack involving the optic nerve or the spinal cord, and at least a second event affecting either topography, and group 2 (negative control group), consisting of a first attack involving the brainstem or the cerebral hemispheres and at least 1 relapse in any topography. Group 3 was composed of patients with NMO according to the 2006 revised diagnostic criteria. Serum NMO-IgG was determined by indirect immunofluorescence. A total of 3.1 of the group 1 patients were positive for NMO-IgG in comparison to 3.9% of group 2 and 44.5% of group 3, NMO. One of the positive patients in group 1 evolved to NMO. NMO-IgG determination is crucial in detecting patients who will develop NMO; however, its value as a routine test in cases presenting with symptoms of the type seen in MS is low, and should only be performed in those patients in which the initial diagnosis is not clear.
    Neurology 05/2012; 78(20):1608-11. · 8.30 Impact Factor
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    ABSTRACT: Multifocal progressive leukoencephalopathy (PML) is associated with JC virus (JCV) seropositivity, past immunosuppression, and natalizumab treatment for two years or more. The aim of our study was to investigate the rate of treatment discontinuation after stratifying for the three risk factors in a group of 104 natalizumab-treated patients with relapsing-remitting multiple sclerosis. We investigated JCV serological status in our population. We then divided patients into groups according to their PML risk. Treatment indication was reassessed. Of the patients, 64 (61.5%) were JCV seropositive. Amongst seropositive patients on natalizumab for 2 years or more, 10 had received immunosuppression (group A), and 38 had not (group B). After an informed and shared decision-making process, 6/10 (60%) from group A compared with 9/38 (23.7%) from group B discontinued treatment (p=0.027). In groups A and B, discontinuation also depended upon doctors' views (p=0.019, group A; p=0.010, group B) and clinical outcomes (p=0.021, group A). No-one from low-intermediate risk groups discontinued. The decision to discontinue natalizumab treatment is complex, even when clear PML risk rates are described. Clinical outcomes and doctors' idiosyncrasies play a crucial part in patients' final choice.
    Multiple Sclerosis 03/2012; 18(8):1193-6. · 4.47 Impact Factor

Publication Stats

2k Citations
557.84 Total Impact Points


  • 2012–2014
    • VHIR Vall d’Hebron Research Institute
      Barcino, Catalonia, Spain
  • 2013
    • Universidad de Las Palmas de Gran Canaria
      Las Palmas, Canary Islands, Spain
  • 2009–2013
    • Autonomous University of Barcelona
      • Department of Medicine
      Cerdanyola del Vallès, Catalonia, Spain
  • 1993–2013
    • University Hospital Vall d'Hebron
      • • Department of Neurology
      • • Unitat de Neuroinmunologia Clínica
      Barcino, Catalonia, Spain
  • 2011
    • IMIM Hospital del Mar Medical Research Institute
      Barcino, Catalonia, Spain
  • 2006
    • Hospital Clinica Benidorm
      Benidorm, Valencia, Spain
  • 2000
    • Hospital de Barcelona. SCIAS
      Barcino, Catalonia, Spain