Showing papers by "Marco Salvetti published in 2014"

Effects of Bacille Calmette-GuÉrin after the first demyelinating event in the CNS

Abstract: Objective: To evaluate Bacille Calmette-Guerin (BCG) effects after clinically isolated syndromes (CIS). Methods: In a double-blind, placebo-controlled trial, participants were randomly assigned to receive BCG or placebo and monitored monthly with brain MRI (6 scans). Both groups then entered a preplanned phase with IM interferon-β-1a for 12 months. From month 18 onward, the patients took the disease-modifying therapies (DMTs) that their neurologist considered indicated in an open-label extension phase lasting up to 60 months. Results: Of 82 randomized subjects, 73 completed the study (33 vaccinated and 40 placebo). During the initial 6 months, the number of cumulative lesions was significantly lower in vaccinated people. The relative risks were 0.541 (95% confidence interval [CI] 0.308–0.956; p = 0.03) for gadolinium-enhancing lesions (the primary endpoint), 0.364 (95% CI 0.207–0.639; p = 0.001) for new and enlarging T2-hyperintense lesions, and 0.149 (95% CI 0.046–0.416; p = 0.001) for new T1-hypointense lesions. The number of total T1-hypointense lesions was lower in the BCG group at months 6, 12, and 18: mean changes from baseline were −0.09 ± 0.72 vs 0.75 ± 1.81 ( p = 0.01), 0.0 ± 0.83 vs 0.88 ± 2.21 ( p = 0.08), and −0.21 ± 1.03 vs 1.00 ± 2.49 ( p = 0.02). After 60 months, the cumulative probability of clinically definite multiple sclerosis was lower in the BCG + DMT arm (hazard ratio = 0.52, 95% CI 0.27–0.99; p p = 0.04). Conclusions: Early BCG may benefit CIS and affect its long-term course. Classification of evidence: BCG, as compared to placebo, was associated with significantly reduced development of gadolinium-enhancing lesions in people with CIS for a 6-month period before starting immunomodulating therapy (Class I evidence).

Guidelines on the clinical use for the detection of neutralizing antibodies (NAbs) to IFN beta in multiple sclerosis therapy: report from the Italian Multiple Sclerosis Study group

Abstract: Interferon beta (IFNβ) was the first specific disease-modifying treatment licensed for relapsing-remitting multiple sclerosis, and is still one of the most commonly prescribed treatments. A strong body of evidence supports the effectiveness of IFNβ preparations in reducing the annual relapse rate, magnetic resonance (MRI) disease activity and disease progression. However, the development of binding/neutralizing antibodies (BAbs/NAbs) during treatment negatively affects clinical and MRI outcomes. Therefore, guidelines for the clinical use for the detection of NAbs in MS may result in better treatment of these patients. In October 2012, a panel of Italian neurologists from 17 MS clinics convened in Milan to review and discuss data on NAbs and their clinical relevance in the treatment of MS. In this paper, we report the panel’s recommendations for the use of IFNβ Nabs detection in the early identification of IFNβ non-responsiveness and the management of patients on IFNβ treatment in Italy, according to a model of therapeutically appropriate care.

Noise in multiple sclerosis: unwanted and necessary

Abstract: As our knowledge about the etiology of multiple sclerosis (MS) increases, deterministic paradigms appear insufficient to describe the pathogenesis of the disease, and the impression is that stochastic phenomena (i.e. random events not necessarily resulting in disease in all individuals) may contribute to the development of MS. However, sources and mechanisms of stochastic behavior have not been investigated and there is no proposed framework to incorporate nondeterministic processes into disease biology. In this report, we will first describe analogies between physics of nonlinear systems and cell biology, showing how small-scale random perturbations can impact on large-scale phenomena, including cell function. We will then review growing and solid evidence showing that stochastic gene expression (or gene expression “noise”) can be a driver of phenotypic variation. Moreover, we will describe new methods that open unprecedented opportunities for the study of such phenomena in patients and the impact of this information on our understanding of MS course and therapy.

Shared environmental effects on multiple sclerosis susceptibility: conflicting evidence from twin studies

Abstract: Sir, We read with interest the paper by Westerlind et al. (2014) on the familial risk in multiple sclerosis. They applied an extended family design to estimate familial risks for multiple sclerosis, and used a twin approach to quantify the contributions of genetic and environmental factors in shaping individual susceptibility to the disease. The correlations in susceptibility of monozygotic (MZ) and dizygotic (DZ) twins (‘tetrachoric correlations’ under the ‘liability-threshold’ model, which provide information on magnitude of genetic and environmental components; Neale and Cardon, 1992) disconfirmed shared environmental effects, in favour of genetic and unshared (individual-specific) environmental influences in …

Erratum: Guidelines on the clinical use for the detection of neutralizing antibodies (NAbs) to IFN beta in multiple sclerosis therapy: Report from the Italian Multiple Sclerosis Study group (Neurological Sciences (2014))

Abstract: Antonio Bertolotto • Marco Capobianco • Maria Pia Amato • Elisabetta Capello • Ruggero Capra • Diego Centonze • Maria Di Ioia • Antonio Gallo • Luigi Grimaldi • Luisa Imberti • Alessandra Lugaresi • Chiara Mancinelli • Maria Giovanna Marrosu • Lucia Moiola • Enrico Montanari • Silvia Romano • Luigina Musu • Damiano Paolicelli • Francesco Patti • Carlo Pozzilli • Silvia Rossi • Marco Salvetti • Gioachino Tedeschi • Maria Rosaria Tola • Maria Trojano • Mauro Zaffaroni • Simona Malucchi

Screening for neurotropic viruses in cerebrospinal fluid of patients with multiple sclerosis and other neurological diseases

Abstract: The paper by Virtanen et al.1 strengthens the association of herpes viruses with multiple sclerosis (MS). The correlation between the presence of Epstein Barr virus (EBV)/Herpes Virus 6 (HHV-6) DNA in cerebrospinal fluid (CSF) and number of contrast enhancing lesions (CELs) on magnetic resonance imaging (MRI) is of interest and mirrors our results from a screening for neurotropic viruses in cerebrospinal fluid of patients with MS and other neurological diseases. We performed PCR for herpes simplex virus 1 (HSV1), herpes simplex virus 2 (HSV2), cytomegalovirus (CMV), varicella zoster virus (VZV), HHV6, JC virus (JCV) and EBV on CSF samples from 159 patients who had had a lumbar puncture for diagnostic purposes. All CSF samples were analyzed using a commercial RHA CNS kit (Labo Bio-medical Products) for the detection of cell-free and cell-associated viral nucleic acids. Patients were then grouped according to their final diagnosis: 60 with MS (58 relapsing–remitting [RR] and two primary progressive [PP]; mean age 37±13 years, 40 females, 20 males), 48 with other inflammatory diseases (OIND; mean age 57±17 years, 23 females, 25 males), and 51 with other non-inflammatory diseases (NIND; mean age 56±18 years, 43 females, 8 males). Gadolinium-enhanced MRI was performed in all patients within 10 days of CSF sampling. In the MS group, 14 patients had a positive PCR for EBV, two for HSV1, three for HSV2 and one for HHV6. In OIND patients, 12 had positive PCR for EBV, two for HSV1, three for HSV2, four for CMV, one for JCV and four for HHV6. In NIND patients, two had positive PCR for EBV, one for HHV6 and one for VZV. The frequency of viral DNA in CSF was comparable among MS and OIND groups. A significant bias in the distribution of EBV was observed in MS and OIND groups with respect to NIND (p = 0.011 at Fisher’s exact test), while CMV infection was more frequent in OIND patients (p = 0.036 at Fisher’s exact test). In patients with MS we observed an excess of large T2 lesions at MRI in cases with EBV DNA in CSF: T2 lesions larger than 10 mm were present in six out 14 EBVpositive and five out 46 EBV-negative patients (p = 0.01 at Fisher’s exact test). This finding was not found in OIND patients; it was also independent of the cell count in CSF, which was higher in OIND than in MS patients (p = 0.02 at Mann–Whitney U test), but was comparable between EBV-positive and EBV-negative MS patients. Thus, the relationship between lesion size and EBV-positive PCR seems not to reflect a non-specific recruitment of leucocytes in the central nervous system in the context of amplified inflammation. The increased chance of detecting EBV DNA in MS patients with more active lesions is instead in accord with Jacobson’s group’s finding1 (at least as far as EBV is concerned) and supports evidence of intrathecal reactivation and virus-driven immunopathogenic response in MS.2,3

Effects of the Bacillus Calmette-Guérin (BCG) Vaccine in the Demyelinating Disease of the Central Nervous System

Abstract: Experimental and epidemiological evidence suggests the benefit of exposure to microbial products (in the absence of infection, e.g., through vaccination) in multiple sclerosis (MS). In a pilot study, the bacillus Calmette-Guerin (BCG) vaccine was safe and effective in reducing disease activity as measured using magnetic resonance imaging (MRI), and in reducing the risk of developing persistent T1-hypointense lesions (“black holes,” an expression of tissue damage) in patients with MS. A placebo-controlled trial in people with clinically isolated syndrome (the onset, generally reversible, of MS) supported the findings of the pilot study. In that study, we observed a benefit on disease activity at MRI, a reduced risk of BH development, and a reduced risk of conversion to clinically definite MS over 5 years, during which time the patients took interferon beta starting six months after BCG or placebo. We suggest the use of BCG immediately after disease onset. Even the possible extension to people at risk of MS might be envisioned, being that the adjuvant approach is safe, cheap, and convenient.

Effects of Bacille Calmette-GuÉrin after the first demyelinating event in the CNSAuthor Response

Abstract: I read the article on Bacille Calmette-Guerin (BCG) reducing the likelihood of developing multiple sclerosis (MS) after an event of clinically isolated syndrome.1 BCG upregulates Notch-1 signaling through a nitric oxide–mediated pathway in macrophages.2 Notch signaling appears to be involved in the pathogenesis of MS; Notch receptors are abundantly expressed in inflammatory and demyelinating lesions as well as in experimental autoimmune encephalomyelitis (EAE).3 Modulation of Notch signaling …

Epstein barr virus genotipic variants and uses thereof as risk predictors, biomarkers and therapeutic targets in multiple sclerosis

Abstract: The present invention relates to a nucleic acid coding for a variant of the Epstein Barr nuclear antigen 2 (EBNA2) for use as a biomarker for predicting the risk of developing multiple sclerosis and/or for screening and/or for the diagnosis and/or prognosis of multiple sclerosis, and to an in vitro method for predicting the risk of developing and/or for screening for multiple sclerosis and/or for the diagnosis and/or prognosis of multiple sclerosis in a subject, comprising the detection of the presence of said nucleic acid.