Publications by authors named "Pietro Iaffaldano"

35 Publications

Risk of Persistent Disability in Patients With Pediatric-Onset Multiple Sclerosis.

JAMA Neurol 2021 May 3. Epub 2021 May 3.

Multiple Sclerosis Center, Gallarate Hospital, ASST Valle Olona, Gallarate (VA), Italy.

Importance: Availability of new disease-modifying therapies (DMTs) and changes of therapeutic paradigms have led to a general improvement of multiple sclerosis (MS) prognosis in adults. It is still unclear whether this improvement also involves patients with pediatric-onset MS (POMS), whose early management is more challenging.

Objective: To evaluate changes in the prognosis of POMS over time in association with changes in therapeutic and managing standards.

Design, Setting, And Participants: Retrospective, multicenter, observational study. Data were extracted and collected in May 2019 from the Italian MS Registry, a digital database including more than 59 000 patients. Inclusion criteria were MS onset before age 18 years, diagnosis before January 2014, and disease duration of at least 3 years. Exclusion criteria were primary progressive MS, Expanded Disability Status Scale (EDSS) score of at least 8 one year after onset, unavailability of diagnosis date, and less than 2 EDSS score evaluations. Eligible patients were 4704 patients with POMS. According to these criteria, we enrolled 3198 patients, excluding 1506.

Exposures: We compared time to reach disability milestones by epoch of MS diagnosis (<1993, 1993-1999, 2000-2006, and 2007-2013), adjusting for possible confounders linked to EDSS evaluations and clinical disease activity. We then analyzed the difference among the 4 diagnosis epochs regarding demographic characteristics, clinical disease activity at onset, and DMTs management.

Main Outcomes And Measures: Disability milestones were EDSS score 4.0 and 6.0, confirmed in the following clinical evaluation and in the last available visit.

Results: We enrolled 3198 patients with POMS (mean age at onset, 15.2 years; 69% female; median time to diagnosis, 3.2 years; annualized relapse rate in first 1 and 3 years, 1.3 and 0.6, respectively), with a mean (SD) follow-up of 21.8 (11.7) years. Median survival times to reach EDSS score of 4.0 and 6.0 were 31.7 and 40.5 years. The cumulative risk of reaching disability milestones gradually decreased over time, both for EDSS score of 4.0 (hazard ratio [HR], 0.70; 95% CI, 0.58-0.83 in 1993-1999; HR, 0.48; 95% CI, 0.38-0.60 in 2000-2006; and HR, 0.44; 95% CI, 0.32-0.59 in 2007-2013) and 6.0 (HR, 0.72; 95% CI, 0.57-0.90; HR, 0.44; 95% CI, 0.33-0.60; and HR, 0.30; 0.20-0.46). In later diagnosis epochs, a greater number of patients with POMS were treated with DMTs, especially high-potency drugs, that were given earlier and for a longer period. Demographic characteristics and clinical disease activity at onset did not change significantly over time.

Conclusions And Relevance: In POMS, the risk of persistent disability has been reduced by 50% to 70% in recent diagnosis epochs, probably owing to improvement in therapeutic and managing standards.
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http://dx.doi.org/10.1001/jamaneurol.2021.1008DOI Listing
May 2021

Early treatment delays long-term disability accrual in RRMS: Results from the BMSD network.

Mult Scler 2021 Apr 26:13524585211010128. Epub 2021 Apr 26.

Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari Aldo Moro, Bari, Italy.

Background: The optimal timing of treatment starts for achieving the best control on the long-term disability accumulation in multiple sclerosis (MS) is still to be defined.

Objective: The aim of this study was to estimate the optimal time to start disease-modifying therapies (DMTs) to prevent the long-term disability accumulation in MS, using a pooled dataset from the Big Multiple Sclerosis Data (BMSD) network.

Methods: Multivariable Cox regression models adjusted for the time to first treatment start from disease onset (in quintiles) were used. To mitigate the impact of potential biases, a set of pairwise propensity score (PS)-matched analyses were performed. The first quintile, including patients treated within 1.2 years from onset, was used as reference.

Results: A cohort of 11,871 patients (median follow-up after treatment start: 13.2 years) was analyzed. A 3- and 12-month confirmed disability worsening event and irreversible Expanded Disability Status Scale (EDSS) 4.0 and 6.0 scores were reached by 7062 (59.5%), 4138 (34.9%), 3209 (31.1%), and 1909 (16.5%) patients, respectively. The risk of reaching all the disability outcomes was significantly lower ( < 0.0004) for the first quintile patients' group.

Conclusion: Real-world data from the BMSD demonstrate that DMTs should be commenced within 1.2 years from the disease onset to reduce the risk of disability accumulation over the long term.
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http://dx.doi.org/10.1177/13524585211010128DOI Listing
April 2021

Treatment Switching and Discontinuation Over 20 Years in the Big Multiple Sclerosis Data Network.

Front Neurol 2021 17;12:647811. Epub 2021 Mar 17.

Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.

Although over a dozen disease modifying treatments (DMTs) are available for relapsing forms of multiple sclerosis (MS), treatment interruption, switching and discontinuation are common challenges. The objective of this study was to describe treatment interruption and discontinuation in the Big MS data network. We merged information on 269,822 treatment episodes in 110,326 patients from 1997 to 2016 from five clinical registries in this cohort study. Treatment stop was defined as a clinician recorded DMT end for any reason and included treatment interruptions, switching to alternate DMTs and long-term or permanent discontinuations. The incidence of DMT stopping cross the full observation period was lowest in FTY (19.7 per 100 person-years (PY) of treatment; 95% CI 19.2-20.1), followed by NAT (22.6/100 PY; 95% CI 22.2-23.0), IFNβ (23.3/100 PY; 95% CI 23.2-23.5). Of the 184,013 observed DMT stops, 159,309 (86.6%) switched to an alternate DMT within 6 months. Reasons for stopping a drug were stable during the observation period with lack of efficacy being the most common reason followed by lack of tolerance and side effects. The proportion of patients continuing on most DMTs were similarly stable until 2014 and 2015 when drop from 83 to 75% was noted. DMT stopping reasons and rates were mostly stable over time with a slight increase in recent years, with the availability of more DMTs. The overall results suggest that discontinuation of MS DMTs is mostly due to DMT properties and to a lesser extent to risk management and a competitive market.
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http://dx.doi.org/10.3389/fneur.2021.647811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010264PMC
March 2021

Longitudinal Evaluation of Serum MOG-IgG and AQP4-IgG Antibodies in NMOSD by a Semiquantitative Ratiometric Method.

Front Neurol 2021 8;12:633115. Epub 2021 Mar 8.

Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro", Bari, Italy.

Immunoadsorption (IA) is an antibody-depleting therapy used to treat neuromyelitis optica spectrum disorder (NMOSD) associated to antiaquaporin 4 (anti-AQP4-IgG) and antimyelin oligodendrocyte glycoprotein (anti-MOG-IgG) serum autoantibodies. Our aim was to evaluate longitudinal changes of serum MOG-IgG and AQP4-IgG antibody titer and to correlate it with the clinical status. Autoantibody titer and clinical features of two MOG-IgG+/AQP4-IgG- and two AQP4-IgG+/MOG-IgG- patients with NMOSD were collected at baseline (T0), after 6 IA courses (T1), and then 2 weeks (T2) and 6 months after treatment (T3). A fluorescent ratiometric assay was used for a quantitative detection of MOG and AQP4 antibodies, based on HEK-293 cells transfected with the full-length hMOG fused to GFP or h-AQP4-M23 isoform fused to m-cherry, respectively. We defined the antibody titer as MOG quantitative ratio (MOGqr) and AQP4 quantitative ratio (AQP4qr). In Case 1, the MOGqr dropped from 0.98 at T0 to 0.14 at T3, and in Case 2, it decreased from 0.96 at T0 to undetectable at T3. In Case3, the AQP4qr remained high: 0.90 at T0 and 0.92 at T3. In Case 4, the AQP4qr decreased from 0.50 at T0 to undetectable at T3. Complete recovery was found in Cases 1, 2, and 4. Semiquantitative ratiometric method accurately detects even slight variation of MOG-IgG and AQP4-IgG titer, suggesting it may be useful to monitor the antibody titer during the disease course and maintenance immunotherapy.
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http://dx.doi.org/10.3389/fneur.2021.633115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982799PMC
March 2021

Long-term comparative analysis of no evidence of disease activity (NEDA-3) status between multiple sclerosis patients treated with natalizumab and fingolimod for up to 4 years.

Neurol Sci 2021 Mar 6. Epub 2021 Mar 6.

Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro", Piazza G. Cesare 11, 70124, Bari, Italy.

Background: Comparative effectiveness of natalizumab and fingolimod over a follow-up longer than 2 years has been not addressed yet.

Objectives: To compare the effect on no evidence of disease activity (NEDA-3) in relapsing-remitting multiple sclerosis (RRMS) patients treated with natalizumab or fingolimod for at least 4 years.

Methods: We included RRMS patients switched from first-line agents to natalizumab or fingolimod. Patients were propensity score (PS)-matched on a 1-to-1 basis. Percentages of patients reaching NEDA-3 status at 2 and 4 years of follow-up were compared using the chi-square test. The risk of not achieving NEDA-3 at 4 years was explored in matched samples by Cox regression models.

Results: We evaluated 174 PS-matched patients. Patients receiving natalizumab reached a NEDA-3 status at 2 and 4 years more frequently than those exposed to fingolimod (63% vs 44%, p=0.037; 45.7% vs 25.8%, p=0.015, respectively). Patients receiving natalizumab were at a significant lower risk of not achieving the NEDA-3 status at 4 years compared to those exposed to fingolimod (hazard ratio (95% confidence interval): 0.54 (0.36-0.80), p=0.002).

Conclusions: Although both medications were effective in patients non-responding to first-line agents, natalizumab seems to be superior to fingolimod in RRMS in obtaining NEDA-3 status at 4 years.
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http://dx.doi.org/10.1007/s10072-021-05127-zDOI Listing
March 2021

Assessing long-term effectiveness of MS treatment - a matter of debate.

Nat Rev Neurol 2021 Apr;17(4):197-198

Department of Basic Medical Sciences, Neurological Sciences and Sense Organs, University of Bari Aldo Moro, Bari, Italy.

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http://dx.doi.org/10.1038/s41582-021-00476-xDOI Listing
April 2021

Defining the course of tumefactive multiple sclerosis: A large retrospective multicentre study.

Eur J Neurol 2021 Apr 12;28(4):1299-1307. Epub 2021 Jan 12.

Department of Clinical and Experimental Epilepsy, Queen Square, UCL Queen Square Institute of Neurology, London, UK.

Background And Purpose: Tumefactive multiple sclerosis (TuMS) (i.e., MS onset presenting with tumefactive demyelinating lesions [TDLs]) is a diagnostic and therapeutic challenge. We performed a multicentre retrospective study to describe the clinical characteristics and the prognostic factors of TuMS.

Methods: One hundred two TuMS patients were included in this retrospective study. Demographic, clinical, magnetic resonance imaging (MRI), laboratory data and treatment choices were collected.

Results: TuMS was found to affect women more than men (female:male: 2.4), with a young adulthood onset (median age: 29.5 years, range: 11-68 years, interquartile range [IQR]: 38 years). At onset, 52% of TuMS patients presented with the involvement of more than one functional system and 24.5% of them with multiple TDLs. TDLs most frequently presented with an infiltrative MRI pattern (38.7%). Cerebrospinal fluid immunoglobulin G oligoclonal bands were often demonstrated (76.6%). In 25.3% of the cases, more than one acute-phase treatment was administered, and almost one-half of the patients (46.6%) were treated with high-efficacy treatments. After a median follow-up of 2.3 years (range: 0.1-10.7 years, IQR: 3.4 years), the median Expanded Disability Status Scale (EDSS) score was 1.5 (range: 0-7, IQR: 2). Independent risk factors for reaching an EDSS score ≥3 were a higher age at onset (odds ratio [OR]: 1.08, 95% confidence interval [CI]: 1.03-1.14, p < 0.01), a higher number of TDLs (OR: 1.67, 95% CI: 1.02-2.74, p < 0.05) and the presence of infiltrative TDLs (OR: 3.34, 95% CI: 1.18-9.5, p < 0.001) at baseline.

Conclusions: The management of TuMS might be challenging because of its peculiar characteristics. Large prospective studies could help to define the clinical characteristics and the best treatment algorithms for people with TuMS.
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http://dx.doi.org/10.1111/ene.14672DOI Listing
April 2021

Transition to secondary progression in relapsing-onset multiple sclerosis: Definitions and risk factors.

Mult Scler 2021 03 19;27(3):430-438. Epub 2020 Nov 19.

Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro," Bari, Italy.

Background: No uniform criteria for a sensitive identification of the transition from relapsing-remitting multiple sclerosis (MS) to secondary-progressive multiple sclerosis (SPMS) are available.

Objective: To compare risk factors of SPMS using two definitions: one based on the neurologist judgment (ND) and an objective data-driven algorithm (DDA).

Methods: Relapsing-onset MS patients ( = 19,318) were extracted from the Italian MS Registry. Risk factors for SPMS and for reaching irreversible Expanded Disability Status Scale (EDSS) 6.0, after SP transition, were estimated using multivariable Cox regression models.

Results: SPMS identified by the DDA ( = 2343, 12.1%) were older, more disabled and with a faster progression to severe disability ( < 0.0001), than those identified by the ND ( = 3868, 20.0%). In both groups, the most consistent risk factors ( < 0.05) for SPMS were a multifocal onset, an age at onset >40 years, higher baseline EDSS score and a higher number of relapses; the most consistent protective factor was the disease-modifying therapy (DMT) exposure. DMT exposure during SP did not impact the risk of reaching irreversible EDSS 6.0.

Conclusion: A DDA definition of SPMS identifies more aggressive progressive patients. DMT exposure reduces the risk of SPMS conversion, but it does not prevent the disability accumulation after the SP transition.
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http://dx.doi.org/10.1177/1352458520974366DOI Listing
March 2021

Clinical effectiveness of different natalizumab interval dosing schedules in a large Italian population of patients with multiple sclerosis.

J Neurol Neurosurg Psychiatry 2020 12 14;91(12):1297-1303. Epub 2020 Oct 14.

Department of Surgical and Medical Sciences Advanced Technologies GF Ingrassia, University of Catania, Catania, Italy

Introduction: Natalizumab (NTZ) is one of the most effective treatment options for multiple sclerosis (MS) treatment. Our study aimed to evaluate the effectiveness of NTZ when administered according to the extended dosing strategy compared with standard 4-weekly administration in a large Italian MS population.

Materials And Methods: This retrospective multicentre study included patients with relapsing-remitting MS (RR-MS) who received NTZ administrations between the 1 June 2012 and the 15 May 2018 and were followed by the 'Italian MS Register'. All patients with MS were stratified into two groups based on NTZ administration schedule: standard interval dosing (SID) patients who received infusions on average from 28 to 32 days (median 30) and extended interval dosing (EID) including patients who have been infused with interval between 33 and 49 days (median 43). Clinical data were assessed at baseline (before starting NTZ), after 12 (T1) and 24 months (T2) of treatment.

Results: Out of 5231 patients with RR-MS screened, 2092 (mean age 43.2±12.0, 60.6% women) were enrolled. A total of 1254 (59.9%) received NTZ according to SID, and 838 (40.1%) according to EID. At 12 and 24 months, no differences in terms of annualised relapse rate and disability status were found between the two groups. Progression index and confirmed disability worsening were similar between the two groups.

Discussion: The use of NTZ with an extended interval schedule showed similar effectiveness compared with SID. Unchanged clinical efficacy of EID schedule may raise the question of a possible advantage in terms of tolerability and safety.
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http://dx.doi.org/10.1136/jnnp-2020-323472DOI Listing
December 2020

Disease-modifying drugs can reduce disability progression in relapsing multiple sclerosis.

Brain 2020 10;143(10):3013-3024

Ospedale Generale Regionale 'F. Miulli', Neurology Unit, Acquaviva delle Fonti (BA), Italy.

An ever-expanding number of disease-modifying drugs for multiple sclerosis have become available in recent years, after demonstrating efficacy in clinical trials. In the real-world setting, however, disease-modifying drugs are prescribed in patient populations that differ from those included in pivotal studies, where extreme age patients are usually excluded or under-represented. In this multicentre, observational, retrospective Italian cohort study, we evaluated treatment exposure in three cohorts of patients with relapsing-remitting multiple sclerosis defined by age at onset: paediatric-onset (≤18 years), adult-onset (18-49 years) and late-onset multiple sclerosis (≥50 years). We included patients with a relapsing-remitting phenotype, ≥5 years follow-up, ≥3 Expanded Disability Status Scale (EDSS) evaluations and a first neurological evaluation within 3 years from the first demyelinating event. Multivariate Cox regression models (adjusted hazard ratio with 95% confidence intervals) were used to assess the risk of reaching a first 12-month confirmed disability worsening and the risk of reaching a sustained EDSS of 4.0. The effect of disease-modifying drugs was assessed as quartiles of time exposure. We found that disease-modifying drugs reduced the risk of 12-month confirmed disability worsening, with a progressive risk reduction in different quartiles of exposure in paediatric-onset and adult-onset patients [adjusted hazard ratios in non-exposed versus exposed >62% of the follow-up time: 8.0 (3.5-17.9) for paediatric-onset and 6.3 (4.9-8.0) for adult-onset, P < 0.0001] showing a trend in late-onset patients [adjusted hazard ratio = 1.9 (0.9-4.1), P = 0.07]. These results were confirmed for a sustained EDSS score of 4.0. We also found that relapses were a risk factor for 12-month confirmed disability worsening in all three cohorts, and female sex exerted a protective role in the late-onset cohort. This study provides evidence that sustained exposure to disease-modifying drugs decreases the risk of disability accumulation, seemingly in a dose-dependent manner. It confirms that the effectiveness of disease-modifying drugs is lower in late-onset patients, although still detectable.
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http://dx.doi.org/10.1093/brain/awaa251DOI Listing
October 2020

Effect of Cladribine on Neuronal Apoptosis: New Insight of In Vitro Study in Multiple Sclerosis Therapy.

Brain Sci 2020 Aug 13;10(8). Epub 2020 Aug 13.

Department of Basic Medical Science, Neuroscience and Sense Organs, School of Medicine, University of Bari Aldo Moro, 70124 Bari, Italy.

Background: Cladribine (2-CdA) can cross the blood-brain barrier, resulting in inhibition of DNA synthesis and repair and disruption of cellular proliferation in actively dividing lymphocytes. No data on effect on neurons are available.

Aim: To study "in vitro" 2-CdA apoptotic effects on neurons in healthy donor and multiple sclerosis patient lymphocytes.

Methods: Neuroblastoma cells were co-cultured with lymphocytes, with and without 2-CdA.

Results: Apoptosis increased in lymphocytes with 2-CdA; increase was also observed when lymphocytes were cultured with neuronal cells. However, neurons were not affected by 2-CdA for apoptosis.

Conclusions: 2-CdA causes peripheral and central lymphocyte death preserving neurons, with a reasonable impact on inflammation and neuroprotection.
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http://dx.doi.org/10.3390/brainsci10080548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464206PMC
August 2020

Durvalumab and multiple sclerosis: a causal link or simple unmasking?

Eur J Clin Pharmacol 2020 Dec 13;76(12):1773-1774. Epub 2020 Jul 13.

Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, Bari, Italy.

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http://dx.doi.org/10.1007/s00228-020-02959-0DOI Listing
December 2020

Seroconversion and indolent course of COVID-19 in patients with multiple sclerosis treated with fingolimod and teriflunomide.

J Neurol Sci 2020 09 4;416:117011. Epub 2020 Jul 4.

Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari "Aldo Moro" Policlinico, Italy Piazza Umberto I, Bari, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.jns.2020.117011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339938PMC
September 2020

Effectiveness of fingolimod in real-world relapsing-remitting multiple sclerosis Italian patients: the GENIUS study.

Neurol Sci 2020 Oct 21;41(10):2843-2851. Epub 2020 Apr 21.

Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari Aldo Moro, Bari, Italy.

Background: Fingolimod is the first oral agent approved for treatment of relapsing-remitting multiple sclerosis (RRMS). We aimed to evaluate fingolimod effectiveness in a real-world sample of RRMS patients.

Methods: A retrospective, multicentre study in patients treated with fingolimod, whom clinical and radiological data were collected in the 2 years preceding and following the initiation of fingolimod.

Results: Out of 414 patients, 56.8% received prior first-line injectable disease-modifying therapies, 25.4% were previously treated with natalizumab, 1.2% with immunosuppressant agents, and 16.7% were treatment naive. The annualized relapse rate decreased by 65% in the first year and by 70% after two years of treatment. Age ≤ 40 years, ≥ 1 relapse in the 24 months before fingolimod initiation and previous treatment with natalizumab were risk factors for relapses. Overall, 67.9% patients had no evidence of disease activity (NEDA-3) after 1 year and 54.6% after 2 years of treatment. A higher proportion of naïve (81.2% in 1 year and 66.7% after 2 years) or first-line injected patients (70.2% and 56.6%) achieved NEDA-3 than those previously treated with natalizumab (54.3% and 42.9%).

Conclusions: Fingolimod appeared to be effective in naive patients and after first-line treatment failure in reducing risk of relapse and disease activity throughout the 2-year follow-up.
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http://dx.doi.org/10.1007/s10072-020-04380-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479005PMC
October 2020

Retrospectively acquired cohort study to evaluate the long-term impact of two different treatment strategies on disability outcomes in patients with relapsing multiple sclerosis (RE.LO.DI.MS): data from the Italian MS Register.

J Neurol 2019 Dec 18;266(12):3098-3107. Epub 2019 Sep 18.

Multiple Sclerosis Center, Hospital of Gallarate, Gallarate, Italy.

Background: The increase in disease-modifying drugs (DMDs) allows individualization of treatment in relapsing multiple sclerosis (RMS); however, the long-term impact of different treatment sequences is not well established. This is particularly relevant for MS patients who may need to postpone more aggressive DMD strategies.

Objective: To evaluate different therapeutic strategies and their long-term outcomes, measured as relapses and confirmed disability progression (CDP), in MS 'real-world' settings.

Methods: Multicentre, observational, retrospectively acquired cohort study evaluating the long-term impact of different treatment strategies on disability outcomes in patients with RMS in the Italian MS Register.

Results: We evaluated 1152 RMS-naïve patients after propensity-score adjustment. Patients included were receiving: interferon beta-1a (IFN-β1a) 44 µg switching to fingolimod (FTY; IFN-switchers; n = 97); FTY only (FTY-stayers; n = 157); IFN-β1a only (IFN-stayers; n = 849). CDP and relapses did not differ between FTY-stayers and IFN-switchers [HR (95% CI) 0.99 (0.48-2.04), p = 0.98 and 0.81 (0.42-1.58), p = 0.55, respectively]. However, IFN-stayers showed increased risk of relapses compared with FTY-stayers [HR (95% CI) 1.46 (1.00-2.12), p = 0.05].

Conclusion: The ideal treatment option for MS is becoming increasingly complex, with the need to balance benefit and risks. Our results suggest that starting with FTY affects the long-term disease outcome similarly to escalating from IFN-β1a to FTY.
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http://dx.doi.org/10.1007/s00415-019-09531-6DOI Listing
December 2019

Lymphocyte Count and Body Mass Index as Biomarkers of Early Treatment Response in a Multiple Sclerosis Dimethyl Fumarate-Treated Cohort.

Front Immunol 2019 14;10:1343. Epub 2019 Jun 14.

Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro", Bari, Italy.

In relapsing Multiple Sclerosis (RMS) patients treated with disease modifying drugs (DMDs), few data are available regarding the biomarkers of treatment response. We aimed to assess the predictive value of lymphocyte count (LC) and Body Mass Index (BMI) for treatment response in a real life setting of dimethyl fumarate (DMF) treated patients. We included in our observational analysis 338 patients who were prescribed DMF in an Italian MS Center. We collected clinical and demographic data at the beginning of DMF (T0), and assessed White Blood Cells (WBC) and LC at T0 and at 3 (T3), 6 (T6), 9 (T9), and 12 (T12) months. Gadolinium enhancing (Gd+), new T2 lesions and relapses within the first year of treatment (T12) were recorded in order to evaluate clinical activity at 12 months. Analysis of correlation was performed to correlate WBC, LC and BMI with clinical and radiological responses. We evaluated whether BMI or LC can predict treatment response by using multivariate logistic regression models at each follow-up. Our cohort was followed up for a mean period of 19.8 ± 6.8 months. The mean BMI at baseline was 24.19 ± 4.48. The multivariate models gave as predictive factors for Gd+ lesions at T12, LC at T3 (OR = 1.003, 95% CI = 1.00-1.07; = 0.046) and baseline BMI (OR = 0.71, 95% CI = 0.52-0.98; = 0.037). Predictive factors for new T2 lesions at T12 were LC at T3 (OR = 1.01 95%CI = 1.00-1.95; = 0.005) and baseline BMI (OR = 0.99, 95% CI = 0.98-1.00; = 0.026). In our real life-experience, BMI and LC may be early biomarkers to predict treatment response during DMF.
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http://dx.doi.org/10.3389/fimmu.2019.01343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587065PMC
November 2020

Post-natalizumab disease reactivation in multiple sclerosis: systematic review and meta-analysis.

Ther Adv Neurol Disord 2019 29;12:1756286419837809. Epub 2019 Mar 29.

Biogen Italia S.r.l., Milan, Italy.

Background: Natalizumab (NTZ) is sometimes discontinued in patients with multiple sclerosis, mainly due to concerns about the risk of progressive multifocal leukoencephalopathy. However, NTZ interruption may result in recrudescence of disease activity.

Objective: The objective of this study was to summarize the available evidence about NTZ discontinuation and to identify which patients will experience post-NTZ disease reactivation through meta-analysis of existing literature data.

Methods: PubMed was searched for articles reporting the effects of NTZ withdrawal in adult patients (⩾18 years) with relapsing-remitting multiple sclerosis (RRMS). Definition of disease activity following NTZ discontinuation, proportion of patients who experienced post-NTZ disease reactivation, and timing to NTZ discontinuation to disease reactivation were systematically reviewed. A generic inverse variance with random effect was used to calculate the weighted effect of patients' clinical characteristics on the risk of post-NTZ disease reactivation, defined as the occurrence of at least one relapse.

Results: The original search identified 205 publications. Thirty-five articles were included in the systematic review. We found a high level of heterogeneity across studies in terms of sample size (10 to 1866 patients), baseline patient characteristics, follow up (1-24 months), outcome measures (clinical and/or radiological), and definition of post-NTZ disease reactivation or rebound. Clinical relapses were observed in 9-80% of patients and peaked at 4-7 months, whereas radiological disease activity was observed in 7-87% of patients starting at 6 weeks following NTZ discontinuation. The meta-analysis of six articles, yielding a total of 1183 patients, revealed that younger age, higher number of relapses and gadolinium-enhanced lesions before treatment start, and fewer NTZ infusions were associated with increased risk for post-NTZ disease reactivation ( ⩽ 0.05).

Conclusions: Results from the present review and meta-analysis can help to profile patients who are at greater risk of post-NTZ disease reactivation. However, potential reporting bias and variability in selected studies should be taken into account when interpreting our data.
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http://dx.doi.org/10.1177/1756286419837809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444403PMC
March 2019

Computer-assisted rehabilitation of attention in pediatric multiple sclerosis and ADHD patients: a pilot trial.

BMC Neurol 2018 Jun 8;18(1):82. Epub 2018 Jun 8.

MS Centre, Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro", Bari, Piazza G. Cesare, 11, 70121, Bari, Italy.

Background: The treatment of cognitive deficits is challenging in pediatric onset multiple sclerosis (POMS) and in patients with attention deficit hyperactivity disorder (ADHD). We performed a pilot double-blind RCT to evaluate the efficacy of a home-based computerized-program for retraining attention in two cohorts of POMS and ADHD patients.

Methods: POMS and ADHD patients failing in at least 2/4 attention tests on a neuropsychological battery were randomized to specific or nonspecific computerized training (ST, nST), performed in one-hour sessions, twice/week for 3 months. The primary outcome was the effect of the training on global neuropsychological performances measured by the cognitive impairment index (CII). The efficacy of the intervention was evaluated in each disease group by using repeated measures ANOVA.

Results: Sixteen POMS (9 females, age 15.75 ± 1.74 years) and 20 ADHD (2 females, age 11.19 ± 2.49 years) patients were enrolled. In POMS patients the ST exposure was associated to a significantly more pronounced improvement of the CII (p < 0.0001) and on cognitive test exploring attention, concentration, planning strategies and visuo-spatial memory performances in comparison to nST exposure. In ADHD patients the difference between the ST and nST on the CII was not statistical significant (p = 0.06), but a greater effect of the ST was found only on cognitive test exploring attention and delayed recall of visuo-spatial memory performances.

Conclusions: Our data suggest that a cognitive rehabilitation program that targets attention is a suitable tool for improving global cognitive functioning in POMS patients, whereas it has a less pronounced transfer effect in ADHD patients.

Trial Registration: ClinicalTrials.gov; NCT03190902 ; registration date: June 15, 2017; retrospectively registered.
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http://dx.doi.org/10.1186/s12883-018-1087-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992821PMC
June 2018

Natalizumab reduces serum pro-angiogenic activity in MS patients.

Neurol Sci 2018 Apr 13;39(4):725-731. Epub 2018 Feb 13.

Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro", Piazza G. Cesare 11, 70124, Bari, Italy.

Angiogenesis has been implicated in the pathobiology of multiple sclerosis (MS). Osteopontin exerts a pro-angiogenetic effect and is increased in body fluid of MS patients. To evaluate the effect of 1 year natalizumab treatment on serum pro-angiogenic activity and on plasma osteopontin levels in relapsing (RR) MS patients. Ten RRMS patients scheduled for natalizumab treatment were enrolled and evaluated at baseline and after 1-year natalizumab treatment. Pro-angiogenic activity was assessed by a chick embryo chorioallantoic membrane assay (CAM), osteopontin levels were evaluated by an enzyme-linked immunosorbent assay. Plasma and serum samples of 10 treatment-naïve RRMS and 10 healthy controls (HCs) were used as controls of baseline evaluations. Both treatment-naïve and natalizumab scheduled RRMS patients had higher baseline vessel density (22.0 ± 3.9 and 22.5 ± 2.6, p < 0.0001) and higher osteopontin levels (65.7 ± 24.3 ng/ml and 65.9 ± 16.6 ng/ml, p = 0.019 and p = 0.029, respectively) than HCs (9.0 ± 2.2; 48.5 ± 7.8 ng/ml, respectively). Baseline osteopontin levels and vessel density were significantly correlated (rs = 0.373, p = 0.043). After 1 year of treatment, the number of vessels and the osteopontin levels, were significantly reduced (11.9 ± 2.1, p < 0.005; 49.3 ± 20.0 ng/ml, p = 0.028). Our results suggest that natalizumab could exert its anti-inflammatory properties also by inhibiting the angiogenetic mechanisms in RRMS patients.
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http://dx.doi.org/10.1007/s10072-018-3266-9DOI Listing
April 2018

Long-term follow-up of pediatric MS patients starting treatment with injectable first-line agents: A multicentre, Italian, retrospective, observational study.

Mult Scler 2019 03 24;25(3):399-407. Epub 2018 Jan 24.

Multiple Sclerosis Study Center, Gallarate Hospital, ASST Valle Olona, Via Eusebio Pastori 4, 21013 Gallarate, Italy.

Background: Few data are available on very long-term follow-up of pediatric multiple sclerosis (MS) patients treated with disease modifying treatments (DMTs).

Objectives: To present a long-term follow-up of a cohort of Pediatric-MS patients starting injectable first-line agents.

Methods: Data regarding treatments, annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS) score, and serious adverse event were collected. Baseline characteristics were tested in multivariate analysis to identify predictors of disease evolution.

Results: In total, 97 patients were followed for 12.5 ± 3.3 years. They started therapy at 13.9 ± 2.1 years, 88 with interferons and 9 with copaxone. During the whole follow-up, 82 patients changed therapy, switching to immunosuppressors/second-line treatment in 58% of cases. Compared to pre-treatment phase, the ARR was significantly reduced during the first treatment (from 3.2 ± 2.6 to 0.7 ± 1.5, p < 0.001), and it remained low during the whole follow-up (0.3 ± 0.2, p < 0.001). At last observation, 40% had disability worsening, but EDSS score remained <4 in 89%. One patient died at age of 23 years due to MS. One case of natalizumab-related progressive multifocal encephalopathy (PML) was recorded. Starting therapy before 12 years of age resulted in a better course of disease in multivariate analysis.

Conclusion: Pediatric-MS patients benefited from interferons/copaxone, but the majority had to switch to more powerful drugs. Starting therapy before 12 years of age could lead to a more favorable outcome.
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http://dx.doi.org/10.1177/1352458518754364DOI Listing
March 2019

Gender differences in safety issues during Fingolimod therapy: Evidence from a real-life Relapsing Multiple Sclerosis cohort.

Brain Behav 2017 10 29;7(10):e00804. Epub 2017 Aug 29.

Department of Basic Medical Sciences, Neuroscience and Sense Organs University of Bari" Aldo Moro" Bari Italy.

Objective: Benefits and risks of new therapies in Multiple Sclerosis (MS) must be balanced carefully and tailored to patients. We aimed to describe our experience with Fingolimod (FTY), correlating demographics, clinical and hematological features of the Relapsing MS (RMS) cohort with the occurring Adverse Events (AEs).

Material And Methods: Pretreatment screening tests, cardiological observation, and safety follow-up data were analyzed in 225 RMS patients. Changes in continuous data were analyzed post hoc with Wilcoxon ranks test; categorical variables were examined using McNemar test. Two-way repeated-measures analysis of variance (ANOVA) was used to analyze differences between baseline characteristic of the cohorts and Liver Function Tests (LFT) alterations. Binary logistic regression models were used to identify which of the baseline factors influenced LFT alterations and the occurrence of infections.

Results: During 2 years of follow-up 24 patients (10%) interrupted FTY. Discontinuation most often was due to AEs (n = 14) or breakthrough disease (n = 5). The most frequently AEs were infections (10.6%). After the first year patients showing an infectious episode were mostly female (= .04). The infections did not correlate with the decrease in white blood cells or to lymphocyte count. AST and ALT alterations ​​were observed mostly in males (= .002 and = .01, respectively), and increase in GGT ​​was reported in subjects older at FTY beginning (< .05).

Conclusions: For a patient-centered safety monitoring of FTY, we may apply gender-specific warnings, for the detection of transaminases abnormalities and infectious episodes.
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http://dx.doi.org/10.1002/brb3.804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5651388PMC
October 2017

Prognostic indicators in pediatric clinically isolated syndrome.

Ann Neurol 2017 May;81(5):729-739

Department of Basic Medical Sciences, Neurosciences, and Sense Organs, University of Bari Aldo Moro, Bari, Italy.

Objective: To assess prognostic factors for a second clinical attack and a first disability-worsening event in pediatric clinically isolated syndrome (pCIS) suggestive of multiple sclerosis (MS) patients.

Methods: A cohort of 770 pCIS patients was followed up for at least 10 years. Cox proportional hazard models and Recursive Partitioning and Amalgamation (RECPAM) tree-regression were used to analyze data.

Results: In pCIS, female sex and a multifocal onset were risk factors for a second clinical attack (hazard ratio [HR], 95% confidence interval [CI] = 1.28, 1.06-1.55; 1.42, 1.10-1.84, respectively), whereas disease-modifying drug (DMD) exposure reduced this risk (HR, 95% CI = 0.75, 0.60-0.95). After pediatric onset MS (POMS) diagnosis, age at onset younger than 15 years and DMD exposure decreased the risk of a first Expanded Disability Status Scale (EDSS)-worsening event (HR, 95% CI = 0.59, 0.42-0.83; 0.75, 0.71-0.80, respectively), whereas the occurrence of relapse increased this risk (HR, 95% CI = 5.08, 3.46-7.46). An exploratory RECPAM analysis highlighted a significantly higher incidence of a first EDSS-worsening event in patients with multifocal or isolated spinal cord or optic neuritis involvement at onset in comparison to those with an isolated supratentorial or brainstem syndrome. A Cox regression model including RECPAM classes confirmed DMD exposure as the most protective factor against EDSS-worsening events and relapses as the most important risk factor for attaining EDSS worsening.

Interpretation: This work represents a step forward in identifying predictors of unfavorable course in pCIS and POMS and supports a protective effect of early DMD treatment in preventing MS development and disability accumulation in this population. Ann Neurol 2017;81:729-739.
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http://dx.doi.org/10.1002/ana.24938DOI Listing
May 2017

Treatment decisions in multiple sclerosis - insights from real-world observational studies.

Nat Rev Neurol 2017 Feb 13;13(2):105-118. Epub 2017 Jan 13.

Department of Medicine, University of Melbourne, and Department of Neurology, Royal Melbourne Hospital, Grattan Street, Parkville, VIC 3050, Australia.

The complexity of multiple sclerosis (MS) treatment means that doctors and decision-makers need the best available evidence to make the best decisions for patient care. Randomized controlled trials (RCTs) are accepted as the gold standard for assessing the efficacy and safety of any new drug, but conclusions of these trials do not always aid in daily decision-making processes. Indeed, RCTs are usually conducted in ideal conditions, so can measure efficacy only in restricted and unrepresentative populations. In the past decade, a growing number of MS databases and registries have started to produce long-term outcome data from large cohorts of patients with MS treated with disease-modifying therapies in real-world settings. Such observational studies are addressing issues that are otherwise difficult or impossible to study. In this Review, we focus on the most recently published observational studies designed to identify predictors of poor outcome and treatment response or failure, and to evaluate the relative and long-term effectiveness of currently used MS treatments. We also outline the statistical approaches that are most commonly used to reduce bias and limitations in these studies, and the challenges associated with the use of 'big MS data' to facilitate the implementation of personalized medicine in MS.
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http://dx.doi.org/10.1038/nrneurol.2016.188DOI Listing
February 2017

Natalizumab discontinuation is associated with a rebound of cognitive impairment in multiple sclerosis patients.

J Neurol 2016 Aug 3;263(8):1620-5. Epub 2016 Jun 3.

Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro", Piazza G. Cesare 11, 70124, Bari, Italy.

Natalizumab discontinuation is associated with a disease reactivation in multiple sclerosis (MS) patients. Whether this reactivation involves also cognitive functions is not known to date. To assess the persistence of the effect of natalizumab on cognitive functions 1 year after its discontinuation, we compared the longitudinal changes of cognitive performances in two groups of patients. The interrupters, 30 MS patients, have stopped natalizumab due to PML concern, and the continuers, 28 MS patients, continued the treatment. The cognitive impairment index (CII) was used as main outcome measure. As expected, during the natalizumab treatment, we observed a significant reduction of the relapse rate and the number of gadolinium-enhancing lesions along with a reduction of the CII. After 1 year of discontinuation, the beneficial effect on cognitive functions was lost in the interrupters group, as the mean CII increased in comparison with the mean at the end of natalizumab treatment (12.2 ± 7.9 vs 9.3 ± 8.1, p < 0.0001). As opposite, in the continuers group, the CII further decreased after an additional year of treatment (8.4 ± 5.1 vs 9.8 ± 4.6, p = 0.007). A multivariate logistic regression model revealed as predictors of cognitive worsening male sex, disease duration, and the treatment discontinuation. The worsening of cognitive functions after natalizumab discontinuation goes in parallel with the clinical/radiological disease reactivation. Our data reinforce the hypothesis that, in the short-term, natalizumab exerts its positive impact on cognitive functions by means of its anti-inflammatory properties.
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http://dx.doi.org/10.1007/s00415-016-8177-1DOI Listing
August 2016

Predictors of long-term disability accrual in relapse-onset multiple sclerosis.

Ann Neurol 2016 07 1;80(1):89-100. Epub 2016 Jun 1.

MS Center, Department of Neuroscience, Imaging and Clinical Sciences, G. d'Annunzio University, Chieti, Italy.

Objective: To identify predictors of 10-year Expanded Disability Status Scale (EDSS) change after treatment initiation in patients with relapse-onset multiple sclerosis.

Methods: Using data obtained from MSBase, we defined baseline as the date of first injectable therapy initiation. Patients need only have remained on injectable therapy for 1 day and were monitored on any approved disease-modifying therapy, or no therapy thereafter. Median EDSS score changes over a 10-year period were determined. Predictors of EDSS change were then assessed using median quantile regression analysis. Sensitivity analyses were further performed.

Results: We identified 2,466 patients followed up for at least 10 years reporting post-baseline disability scores. Patients were treated an average 83% of their follow-up time. EDSS scores increased by a median 1 point (interquartile range = 0-2) at 10 years post-baseline. Annualized relapse rate was highly predictive of increases in median EDSS over 10 years (coeff = 1.14, p = 1.9 × 10(-22) ). On-therapy relapses carried greater burden than off-therapy relapses. Cumulative treatment exposure was independently associated with lower EDSS at 10 years (coeff = -0.86, p = 1.3 × 10(-9) ). Furthermore, pregnancies were also independently associated with lower EDSS scores over the 10-year observation period (coeff = -0.36, p = 0.009).

Interpretation: We provide evidence of long-term treatment benefit in a large registry cohort, and provide evidence of long-term protective effects of pregnancy against disability accrual. We demonstrate that high annualized relapse rate, particularly on-treatment relapse, is an indicator of poor prognosis. Ann Neurol 2016;80:89-100.
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http://dx.doi.org/10.1002/ana.24682DOI Listing
July 2016

Fingolimod versus interferon beta/glatiramer acetate after natalizumab suspension in multiple sclerosis.

Brain 2015 Nov 11;138(Pt 11):3275-86. Epub 2015 Sep 11.

4 Department of Neurosciences, Reproductive and Odontostomatological Sciences, University "Federico II", Via Pansini 5, 80131 Napoli, Italy.

The comparative effectiveness of fingolimod versus interferon beta/glatiramer acetate was assessed in a multicentre, observational, prospectively acquired cohort study including 613 patients with relapsing multiple sclerosis discontinuing natalizumab in the Italian iMedWeb registry. First, after natalizumab suspension, the relapse risk during the untreated wash-out period and during the course of switch therapies was estimated through Poisson regression analyses in separated models. During the wash-out period an increased risk of relapses was found in patients with a higher number of relapses before natalizumab treatment (incidence rate ratio = 1.31, P = 0.0014) and in patients discontinuing natalizumab due to lack of efficacy (incidence rate ratio = 2.33, P = 0.0288), patient's choice (incidence rate ratio = 2.18, P = 0.0064) and adverse events (incidence rate ratio = 2.09, P = 0.0084). The strongest independent factors influencing the relapse risk after the start of switch therapies were a wash-out duration longer than 3 months (incidence rate ratio = 1.78, P < 0.0001), the number of relapses experienced during and before natalizumab treatment (incidence rate ratio = 1.61, P < 0.0001; incidence rate ratio = 1.13, P = 0.0118, respectively) and the presence of comorbidities (incidence rate ratio = 1.4, P = 0.0097). Switching to fingolimod was associated with a 64% reduction of the adjusted-risk for relapse in comparison with switching to interferon beta/glatiramer acetate (incidence rate ratio = 0.36, P < 0.0001). Secondly, patients who switched to fingolimod or to interferon beta/glatiramer acetate were propensity score-matched on a 1-to-1 basis at the switching date. In the propensity score-matched sample a Poisson model showed a significant lower incidence of relapses in patients treated with fingolimod in comparison with those treated with interferon beta/glatiramer acetate (incidence rate ratio = 0.52, P = 0.0003) during a 12-month follow-up. The cumulative probability of a first relapse after the treatment switch was significantly lower in patients receiving fingolimod than in those receiving interferon beta/glatiramer acetate (P = 0.028). The robustness of this result was also confirmed by sensitivity analyses in subgroups with different wash-out durations (less or more than 3 months). Time to 3-month confirmed disability progression was not significantly different between the two groups (Hazard ratio = 0.58; P = 0.1931). Our results indicate a superiority of fingolimod in comparison to interferon beta/glatiramer acetate in controlling disease reactivation after natalizumab discontinuation in the real life setting.
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http://dx.doi.org/10.1093/brain/awv260DOI Listing
November 2015

First evidence of in vivo pro-angiogenic activity of cerebrospinal fluid samples from multiple sclerosis patients.

Clin Exp Med 2016 Feb 25;16(1):103-7. Epub 2014 Dec 25.

Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Policlinico - Piazza G. Cesare, 11, 70124, Bari, Italy.

Increased vascular density and endothelial cell proliferation have been demonstrated in multiple sclerosis (MS) white matter, as well as an elevated vascular endothelial growth factor expression was detected in reactive astrocytes of both active and inactive chronic demyelinated lesions and in sera of MS patients during clinical relapses. In this study, we have investigated the angiogenic activity of cerebrospinal fluid (CSF) samples from MS patients with different stages of disease by means of the chick embryo chorioallantoic membrane (CAM), a well-known assay to study angiogenesis in vivo. Results have shown that CSF samples from MS patients induced a significant (p < 0.05) angiogenic response in CAM in comparison with CSF from neurological controls. The vessel density was higher (p < 0.0001) in secondary (23.60 ± 1.14) and primary (23.50 ± 1.87) progressive patients in comparison with relapsing MS (17.25 ± 1.75) and clinically isolated syndrome suggestive of MS (13.00 ± 1.79), and a significant correlation (r = 0.611, p = 0.005) was found between the angiogenic response and disability level. The results of this preliminary report demonstrate for the first time an angiogenic activity in vivo of CSF samples from MS patients and confirm the importance of angiogenesis as a key event in MS pathogenesis and progression.
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http://dx.doi.org/10.1007/s10238-014-0334-1DOI Listing
February 2016

Emotional and neutral verbal memory impairment in Multiple Sclerosis.

J Neurol Sci 2014 Jun 26;341(1-2):28-31. Epub 2014 Mar 26.

Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari Aldo Moro, Bari, Italy. Electronic address:

Background: A defective emotional enhancement of verbal memory (VM) performances has been reported in different neurological diseases.

Objectives: To assess the emotional enhancement of VM in 22 Clinically Isolated Syndrome (CIS) suggestive of Multiple Sclerosis (MS) and 49 Relapsing (RR) MS patients in comparison to 32 Healthy Controls (HC).

Methods: Immediate and delayed recall of VM was assessed using the Selective Reminding Test (SRT). A list of 12 emotionally significant words was used to evaluate the Emotional (E) variants of the SRT. Depressive symptoms were assessed by the Beck Depression Inventory.

Results: The prevalence of depression did not differ between RRMS and CIS patients. Both patient groups showed poorer (p<0.01) VM performances in comparison to HC in all the SRT tasks, but no difference was found between the two patient groups. Emotionally salient words were more (p<0.0001) recalled than neutral words in HC and CIS, but not in RRMS patients, while performing the immediate recall tasks. Delayed recall was not affected by emotional stimuli in both CIS and RR MS groups. The presence of depressive symptoms did not influence the VM performances.

Conclusions: Our results demonstrate a defective emotional enhancement of VM in definite MS and, although to a lesser extent, in CIS patients.
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http://dx.doi.org/10.1016/j.jns.2014.03.038DOI Listing
June 2014

The improvement of cognitive functions is associated with a decrease of plasma Osteopontin levels in Natalizumab treated relapsing multiple sclerosis.

Brain Behav Immun 2014 Jan 30;35:176-81. Epub 2013 Aug 30.

Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari Aldo Moro, Bari, Italy.

Objective: To investigate the effect of two-years Natalizumab treatment on plasma Osteopontin levels, cognitive performances and fatigue in relapsing multiple sclerosis (RRMS) patients.

Methods: Forty-nine RRMS patients scheduled for Natalizumab treatment as second-line therapy were enrolled. Plasma samples of twenty-four treatment-naïve RRMS and 22 healthy controls (HCs) were used as controls of baseline Osteopontin levels. Plasma Osteopontin levels, using an enzyme-linked immunosorbent assay, cognitive functions using the brief repeatable battery, and fatigue, by the fatigue severity scale (FSS), were assessed at baseline and every 12months. A global cognitive impairment index (CII) was calculated for each patient.

Results: Patients scheduled for Natalizumab treatment had higher baseline Osteopontin levels (mean [SD] 65.42 [22.20]ng/ml) (p=0.013) than HCs (53.20 [12.68]ng/ml), but not different from those in the treatment-naïve RRMS group (67.70 [24.23]ng/ml); 30.6% of patients showed a cognitive impairment (failure ⩾3 tests) and 47.6% complained fatigue interfering with daily activities(FSS score ⩾4.5). A significant decrease of mean Osteopontin levels (p<0.005), of mean CII values (p<0.005) and of mean FSS score (p<0.05) was found during the treatment. Baseline Osteopontin levels significantly correlated (p=0.002) with baseline CII values, and the reduction of the CII values during Natalizumab treatment significantly correlated with the decrease of the Osteopontin levels (p<0.05). No correlations were found between Osteopontin levels and FSS score before and during Natalizumab treatment.

Conclusions: Natalizumab treatment reduces plasma Osteopontin levels and improves cognition and fatigue in RRMS patients. The results suggest that the improvement of cognitive functions is associated to a decrease of plasma Osteopontin levels.
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http://dx.doi.org/10.1016/j.bbi.2013.08.009DOI Listing
January 2014

Geographical variations in sex ratio trends over time in multiple sclerosis.

PLoS One 2012 25;7(10):e48078. Epub 2012 Oct 25.

Department of Neuroscience and Sense Organs, University of Bari, Bari, Italy.

Background: A female/male (F/M) ratio increase over time in multiple sclerosis (MS) patients was demonstrated in many countries around the world. So far, a direct comparison of sex ratio time-trends among MS populations from different geographical areas was not carried out.

Objective: In this paper we assessed and compared sex ratio trends, over a 60-year span, in MS populations belonging to different latitudinal areas.

Methods: Data of a cohort of 15,996 (F = 11,290; M = 4,706) definite MS with birth years ranging from 1930 to 1989 were extracted from the international MSBase registry and the New Zealand MS database. Gender ratios were calculated by six decades based on year of birth and were adjusted for the F/M born-alive ratio derived from the respective national registries of births.

Results: Adjusted sex ratios showed a significant increase from the first to the last decade in the whole MS sample (from 2.35 to 2.73; p = 0.03) and in the subgroups belonging to the areas between 83° N and 45° N (from 1.93 to 4.55; p<0.0001) and between 45° N to 35° N (from 1.46 to 2.30; p<0.05) latitude, while a sex ratio stability over time was found in the subgroup from areas between 12° S and 55° S latitude. The sex ratio increase mainly affected relapsing-remitting (RR) MS.

Conclusions: Our results confirm a general sex ratio increase over time in RRMS and also demonstrate a latitudinal gradient of this increase. These findings add useful information for planning case-control studies aimed to explore sex-related factors responsible for MS development.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0048078PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3485003PMC
May 2013