[Show abstract][Hide abstract] ABSTRACT: We aimed to investigate potential associations between human leukocyte antigen (HLA) class I and class II alleles and the development of anaphylactic/anaphylactoid reactions in patients with multiple sclerosis (MS) treated with natalizumab.
HLA class I and II genotyping was performed in patients with MS who experienced anaphylactic/anaphylactoid reactions and in patients who did not develop infusion-related allergic reactions following natalizumab administration.
A total of 119 patients with MS from 3 different cohorts were included in the study: 54 with natalizumab-related anaphylactic/anaphylactoid reactions and 65 without allergic reactions. HLA-DRB1*13 and HLA-DRB1*14 alleles were significantly increased in patients who developed anaphylactic/anaphylactoid reactions (p M-H = 3 × 10(-7); odds ratio [OR]M-H = 8.96, 95% confidence interval [CI] = 3.40-23.64), with a positive predictive value (PPV) of 82%. In contrast, the HLA-DRB1*15 allele was significantly more represented in patients who did not develop anaphylactic/anaphylactoid reactions to natalizumab (p M-H = 6 × 10(-4); ORM-H = 0.2, 95% CI = 0.08-0.50), with a PPV of 81%.
HLA-DRB1 genotyping before natalizumab treatment may help neurologists to identify patients with MS at risk for developing serious systemic hypersensitivity reactions associated with natalizumab administration.
[Show abstract][Hide abstract] ABSTRACT: Background
In a previous proteomics study using pooled cerebrospinal fluid (CSF) samples, we proposed apolipoprotein AI, apolipoprotein AIV, vitronectin, plasminogen, semaphorin 7A, and ala-ß-his-dipeptidase as candidate biomarkers associated with the conversion to clinically definite multiple sclerosis (CDMS) in patients with clinically isolated syndromes (CIS). Here, we aimed to validate these results in individual CSF samples using alternative techniques.Methods
In a first replication study, levels of apolipoproteins AI and AIV, vitronectin, and plasminogen were measured by ELISA in CSF and serum of 56 CIS patients (29 patients who converted to CDMS (MS converters) and 27 patients who remained with CIS during follow-up (MS non-converters)) and 26 controls with other neurological disorders. Semaphorin 7A and ala-ß-his-dipeptidase levels were determined by selected reaction monitoring (SRM) in CSF of 36 patients (18 MS converters, 18 non-converters) and 20 controls. In a second replication study, apolipoprotein AI levels were measured by ELISA in CSF of 74 CIS patients (47 MS converters, 27 non-converters) and 50 individual controls, and levels of semaphorin 7A and ala-beta-his-dipeptidase were determined by SRM in 49 patients (24 MS converters, 25 non-converters) and 22 controls.ResultsCSF levels of apolipoprotein AI were increased (P =0.043) and levels of semaphorin 7A and ala-ß-his-dipeptidase decreased (P =4.4¿×¿10¿10 and P =0.033 respectively) in MS converters compared to non-converters. No significant differences were found in serum levels for apolipoproteins AI and AIV, vitronectin, and plasminogen. Findings with semaphorin 7A and ala-ß-his-dipeptidase were also validated in the second replication study, and CSF levels for these two proteins were again decreased in MS converters versus non-converters (P =1.2¿×¿10¿4 for semaphorin 7A; P =3.7¿×¿10¿8 for ala-ß-his-dipeptidase). Conversely, apolipoprotein AI findings were not replicated and CSF levels for this protein did not significantly differ between groups. Furthermore, CSF semaphorin 7A levels were negatively associated with the number of T2 lesions at baseline and one-year follow-up.Conclusions
These results validate previous findings for semaphorin 7A and ala-ß-his-dipeptidase, and suggest that these proteins play a role as CSF biomarkers associated with the conversion to CDMS in CIS patients.
Journal of Neuroinflammation 11/2014; 11(1):181. · 4.90 Impact Factor
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: The objective of this study is to characterize the timing and extent of radiologic MS disease recurrence during the 24-week natalizumab treatment interruption period in RESTORE. RESTORE was a randomized, partially placebo-controlled exploratory study. Natalizumab-treated patients with no gadolinium-enhancing (Gd+) lesions at screening (n = 175) were randomized 1:1:2 to continue natalizumab (n = 45), switch to placebo (n = 42), or switch to other therapies (n = 88) for 24 weeks. MRI assessments were performed every 4 weeks. Predictors of increased numbers of Gd+ lesions during natalizumab treatment interruption were evaluated. The numbers of Gd+ lesions were compared with retrospectively collected pre-natalizumab MRI reports and data from placebo-treated patients from two historical randomized clinical trials. Gd+ lesions were detected in 0 % (0/45) of natalizumab patients, 61 % (25/41) of placebo patients, and 48 % (39/81) of other-therapies patients during the randomized treatment period. Gd+ lesions were detected starting at week 12; most were observed at week 16 or later. Thirteen percent (14/107) of patients had >5 Gd+ lesions on ≥1 (of 6) scans during the randomized treatment period versus 7 % (7/107) of patients pre-natalizumab (based on medical record of a single scan). Younger patients and those with more Gd+ lesions pre-natalizumab were more likely to have increased MRI activity. Distribution of total and persistent Gd+ lesions in RESTORE patients was similar to placebo-treated historical control patients. In most patients, recurring radiological disease activity during natalizumab interruption did not exceed pre-natalizumab levels or levels seen in historical control patients.
Journal of Neurology 11/2014; · 3.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Primary and secondary progressive forms of multiple sclerosis (PPMS and SPMS) have different pathological characteristics. However, it is unknown whether neurodegenerative mechanisms are shared. We measured cerebrospinal fluid (CSF) levels of neurofilament (Nf) light and heavy isoforms and N-acetylaspartic acid (NAA) in 21 PP, 10 SPMS patients and 15 non-inflammatory neurological disease controls (NINDC). Biomarkers were related to Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Severity Score (MSSS) over a long period of follow-up [median (interquartile range) 9 (5.5-12.5) years] in 19 PPMS and 4 SPMS patients, and to T2 lesion load, T1 lesion load, and brain parenchymal fraction at the time of lumbar puncture. Nf light was higher in PPMS (p < 0.005) and Nf heavy was increased in both SPMS and PPMS (p < 0.05 and p < 0.01) compared to NINDC, but were comparable between the two MS subtypes. Nf heavy was a predictor of the ongoing disability measured by MSSS (R (2) = 0.17, β = 0.413; p < 0.05). Conversely, Nf light was the only predictor of the EDSS annual increase (R (2) = 0.195, β = 0.441; p < 0.05). The frequency of abnormal biomarkers did not differ between the two MS progressive subtypes. Our data suggest that PP and SPMS likely share similar mechanisms of axonal damage. Moreover, Nf heavy can be a biomarker of ongoing axonal damage. Conversely, Nf light can be used as a prognostic marker for accumulating disability suggesting it as a good tool for possible treatment monitoring in the progressive MS forms.
Journal of Neurology 09/2014; · 3.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Heat shock protein (Hsp)70 is one of the most important stress-inducible proteins. Intracellular Hsp70 not only mediates chaperone-cytoprotective functions but can also block multiple steps in the apoptosis pathway. In addition, Hsp70 is actively released into the extracellular milieu, thereby promoting innate and adaptive immune responses. Thus, Hsp70 may be a critical molecule in multiple sclerosis (MS) pathogenesis and a potential target in this disease due to its immunological and cytoprotective functions. To investigate the role of Hsp70 in MS pathogenesis, we examined its immune and cytoprotective roles using both in vitro and in vivo experimental procedures. We found that Hsp70.1-deficient mice were more resistant to developing experimental autoimmune encephalomyelitis (EAE) compared with their wild-type (WT) littermates, suggesting that Hsp70.1 plays a critical role in promoting an effective myelin oligodendrocyte glycoprotein (MOG)-specific T cell response. Conversely, Hsp70.1-deficient mice that developed EAE showed an increased level of autoreactive T cells to achieve the same production of cytokines compared with the WT mice. Although a neuroprotective role of HSP70 has been suggested, Hsp70.1-deficient mice that developed EAE did not exhibit increased demyelination compared with the control mice. Accordingly, Hsp70 deficiency did not influence the vulnerability to apoptosis of oligodendrocyte precursor cells (OPCs) in culture. Thus, the immunological role of Hsp70 may be relevant in EAE, and specific therapies down-regulating Hsp70 expression may be a promising approach to reduce the early autoimmune response in MS patients.
PLoS ONE 08/2014; 9(8):e105737. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The presence of oligoclonal IgM bands (OCMB) in cerebrospinal fluid (CSF) is an unfavourable prognostic marker in multiple sclerosis. There is no commercial test to investigate OCMB status. However, a sensitive and specific isoelectrofocusing (IEF) and western blot method was described. We aimed to study the inter-centre reproducibility of this technique, a necessary condition for a reliable test to be incorporated into clinical practice.
[Show abstract][Hide abstract] ABSTRACT: Objective
Some previous studies suggest modest to strong effects of 25-hydroxyvitamin D (25(OH)D) on multiple sclerosis (MS) activity. The objective of this study was to explore the mechanistic rationale that may explain potential clinical effects of 25(OH)D.Methods
This study measured serum 25(OH)D levels and global gene expression profiles over a course of up to 2 years in patients starting treatment with interferon beta-1b (IFNB-1b) after a clinically isolated syndrome. MS disease activity was assessed by the number of gadolinium-enhancing lesions present on repeated magnetic resonance imaging (MRIs).ResultsThe number of gadolinium-enhancing lesions was highly significantly associated with 25(OH)D levels. Conducting various systems-level analyses on the molecular level, multiple lines of evidence indicated that 25(OH)D regulates expression dynamics of a large gene–gene interaction system which primarily regulates immune modulatory processes modulating MS activity. The vitamin D response element was significantly enriched in this system, indicating a direct regulation of this gene interaction network through the vitamin D receptor. With increasing 25(OH)D levels, resulting regulation of this system was associated with a decrease in MS activity. Within the complex network of genes that are regulated by 25(OH)D, well-described targets of IFNB-1b and a regulator of sphingosine-1-phosphate bioavailability were found. The 25(OH)D effects on MS activity were additively enhanced by IFNB-1b.InterpretationHere, we provide mechanistic evidence that an unbalanced 25(OH)D gene expression system may affect MS activity. Our findings support a potential benefit of monitoring and managing vitamin D levels (e.g., through supplementation) in early MS patients treated with IFN-beta-1b.
Annals of Clinical and Translational Neurology. 08/2014;
[Show abstract][Hide abstract] 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; · 2.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Multiple sclerosis (MS) is the most common inflammatory, demyelinating, and neurodegenerative disorder of the central nervous system (CNS) in humans. Although the etiology of MS remains unknown, several lines of evidence support the notion that autoimmunity against components of the myelin sheath plays a major role in susceptibility to and development of the disease. At present, there are no approved MS therapies aimed specifically toward downregulating antigen-specific autoreactive immune cells. One antigen-specific approach that appears promising for the treatment of MS is DNA vaccination. This technique has demonstrated efficacy in clinical trials while maintaining safety.Here, we describe the generation of DNA vaccines containing immunologically relevant antigens of MS. Moreover, we present a detailed protocol for the prophylactic and therapeutic administration of DNA vaccines via intramuscular injection targeting on the development of experimental autoimmune encephalomyelitis (EAE), an animal model resembling MS.
[Show abstract][Hide abstract] ABSTRACT: At present, three risk factors for the development of progressive multifocal leukoencephalopathy (PML) in natalizumab-treated patients have been identified: the presence of antibodies against JC virus (JCV); the duration of natalizumab treatment, especially if longer than 2 years; and the use of immunosuppressants prior to receiving natalizumab. The most commonly used strategy to assess the individual PML risk includes serum anti-JCV antibody testing. Based on the knowledge on all known risk factors, an algorithm for PML risk stratification has been proposed, where patients with the highest PML risk are those with positive anti-JCV antibodies, treatment duration longer than 2 years, with or without prior history of immunosuppression. These patients would have an approximate incidence of PML of 11.1 (with prior immunosuppression) or 4.6 (without prior immunosuppression) cases per 1,000 patients treated with natalizumab (and treatment duration longer than 2 years). In this review, new data on PML risk factors and possible new strategies for PML risk stratification are discussed.
[Show abstract][Hide abstract] ABSTRACT: Multiple sclerosis is a chronic, demyelinating and inflammatory disease of the central nervous system that mainly affects young adults. It is characterised by processes involving inflammation, demyelination and axonal destruction, and as a result the pathogenic aspects and response to treatment of the disease vary widely. It is therefore difficult to establish a prognosis for these patients or to determine the effectiveness of the different drugs that are employed. Current clinical research into the development of new biomarkers has advanced a great deal in recent years, especially in the early stages of the disease. Yet, it is essential to further our knowledge about novel markers of the disease, and not only in the more advanced stages, so as to be able to stop disability from progressing and to establish new therapy regimens in these patients. This review presents an update on the information available about the biomarkers that are currently validated and used in multiple sclerosis, together with the possible candidates for utilisation in routine clinical practice.
[Show abstract][Hide abstract] ABSTRACT: IFI16 encodes a nucleic acid-sensor which detects latent EBV and triggers inflammasome activation. We analysed IFI16 variants in two multiple sclerosis (MS) case-control cohorts from Italy and Spain; results were combined with a previous study. A risk variant for celiac disease/rheumatoid arthritis, a polymorphic exon 7 duplication, and a copy number variant (CNV) in the 5' region were genotyped. No significant association was detected, although heterogeneity was noted for the 5' CNV in the Italian plus GeneMSA cohorts and the Spanish sample. Thus, IFI16 variants do not contribute to MS susceptibility, although some heterogeneity may exist for the 5' CNV.
Journal of neuroimmunology 06/2014; · 2.84 Impact Factor