Eleonora Cocco | University of Cagliari (original) (raw)

Papers by Eleonora Cocco

Drug Design, Development and Therapy

Multiple sclerosis (MS) is a complex disease of the central nervous system that can cause permane... more Multiple sclerosis (MS) is a complex disease of the central nervous system that can cause permanent disability in young adults. A large armamentarium is available for its management and is increasing over time. Ozanimod is an oral drug belonging to the sphingosine-1-phosphate receptor (S1PR) modulator family recently approved in different countries for MS with active disease. It selectively modulates S1PR1 and S1PR5 to prevent autoreactive lymphocytes from entering the central nervous system (CNS), where they can determine inflammation and neurodegeneration. Ozanimod was tested in one Phase II and two Phase III pivotal trials and was shown to be effective and well tolerated. Moreover, further investigations, including comparative trials with other S1P modulators and MS disease-modifying drugs, are needed to better define placement in MS treatment. Furthermore, ozanimod is currently under evaluation for inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease, in international phase III studies. This article retraces the itinerary leading to the approval of ozanimod for MS treatment and its peculiarities and potentiality inside the S1PR modulator family.

European Journal of Neurology

Symmetry

The majority of people with Multiple Sclerosis (pwMS), report lower limb motor dysfunctions, whic... more The majority of people with Multiple Sclerosis (pwMS), report lower limb motor dysfunctions, which may relevantly affect postural control, gait and a wide range of activities of daily living. While it is quite common to observe a different impact of the disease on the two limbs (i.e., one of them is more affected), less clear are the effects of such asymmetry on gait performance. The present retrospective cross-sectional study aimed to characterize the magnitude of interlimb asymmetry in pwMS, particularly as regards the joint kinematics, using parameters derived from angle-angle diagrams. To this end, we analyzed gait patterns of 101 pwMS (55 women, 46 men, mean age 46.3, average Expanded Disability Status Scale (EDSS) score 3.5, range 1–6.5) and 81 unaffected individuals age- and sex-matched who underwent 3D computerized gait analysis carried out using an eight-camera motion capture system. Spatio-temporal parameters and kinematics in the sagittal plane at hip, knee and ankle join...

Frontiers in Neurology

Objectives: The aim of this study was to characterize multiple sclerosis (MS) patients exposed to... more Objectives: The aim of this study was to characterize multiple sclerosis (MS) patients exposed to dimethyl fumarate (DMF) and to evaluate the predictors of therapeutic response. In addition, the study offers a picture of how DMF use has changed over the past few years in naive or switcher patients.Methods: In this observational monocentric study, we examined the prescription flow of DMF in MS patients categorized as naive or switchers (for safety/tolerability, ineffectiveness, and de-escalation strategy) from 2015 to 2019. Clinical and magnetic resonance imaging data of DMF-treated patients were analyzed, and NEDA-3 status at 24 months was evaluated by the three assessment components (absence of clinical relapses, no Expanded Disability Status Scale progression, no radiological activity). Determinants of therapeutic response were also evaluated using regression analysis.Results: The sample included 595 MS patients exposed to DMF categorized as naive (158; 26.5%) and switchers for re...

Background: Approximately 60% of people with multiple sclerosis (PwMS) suffer from upper limb dys... more Background: Approximately 60% of people with multiple sclerosis (PwMS) suffer from upper limb dysfunction. Our primary goal is to implement a single-blind, randomized control trial (RCT) designed to compare the effectiveness of an 8-week home-based telerehab virtual reality (VR) program with conventional therapy in PwMS with manual dexterity difficulties. Secondary aims include: a) evaluating the impact of the programs on quality of life after the intervention and a follow up 1 month later; and b) evaluating the impact of the programs on adherence and satisfaction. Methods: Twenty-four PwMS will be recruited to the study which will be conducted at two established MS centers: (1) The Regional Center for Diagnosis and Treatment of Multiple Sclerosis, Binaghi Hospital, Cagliari, Italy; (2) The Multiple Sclerosis Center, Sheba Medical Center, Tel-Hashomer, Israel. Participants will complete a total of three assessments focusing on upper limb functions. Both groups will receive 16 traini...

International Journal of Environmental Research and Public Health

In people with multiple sclerosis (pwMS), fatigue, weakness and spasticity may reduce mobility an... more In people with multiple sclerosis (pwMS), fatigue, weakness and spasticity may reduce mobility and promote sedentary behavior. However, little is known about the existence of possible differences in the way MS modifies the propensity to perform physical activity (PA) in men and women. The present study aimed to partly close this gap by means of quantitative analysis carried out using wearable sensors. Forty-five pwMS (23 F, 22 M, mean age 50.3) and 41 unaffected age- and sex-matched individuals wore a tri-axial accelerometer 24 h/day for 7 consecutive days. Raw data were processed to calculate average number of daily steps, vector magnitude (VM) counts, and percentage of time spent in sedentary behavior and in PA of different intensities (i.e., light and moderate-to-vigorous, MVPA). Women with MS spent more time in sedentary behavior and exhibited a reduced amount of light intensity activity with respect to men, while MVPA was similar across sexes. However, in comparison with unaffe...

Multiple Sclerosis and Related Disorders

Microorganisms

Interleukin 2 (IL-2) is considered a key player in exacerbating multiple sclerosis (MS). Therapie... more Interleukin 2 (IL-2) is considered a key player in exacerbating multiple sclerosis (MS). Therapies targeting its receptor have been developed; however, a resolution of the disease and side effects are still an issue of concern. The involvement of other factors, such as Mycobacterium avium subspecies paratuberculosis (MAP) and envelope protein derived from human endogenous retrovirus type W (HERV-Wenv), in MS pathogenesis has been recently suggested. Here, we investigated the levels of antibodies (Abs) directed against IL-2 and HERV-Wenv in 108 MS patients, 34 patients affected by neuromyelitis optica spectrum disorder (NMOSD), and 137 healthy controls (HCs). Our results show increased levels of Abs specific to IL-2 and HERV-Wenv-su antigens in MS vs. HCs (p < 0.0001 for IL-2, p = 0.0004 for HERV-Wenv) and significantly decreased levels in NMOSD vs. MS. The assessment of different 12-month-long therapies on Abs against IL-2, HERV-Wenv, and MAP lipoarabinomannan (LAM) demonstrated ...

PLOS ONE

Although the etiology of multiple sclerosis is not yet understood, it is accepted that its pathog... more Although the etiology of multiple sclerosis is not yet understood, it is accepted that its pathogenesis involves both autoimmune and neurodegenerative processes, in which the role of autoreactive T-cells has been elucidated. Instead, the contribution of humoral response is still unclear, even if the presence of intrathecal antibodies and B-cells follicle-like structures in meninges of patients has been demonstrated. Several myelin and non-myelin antigens have been identified, but none has been validated as humoral biomarker. In particular autoantibodies against myelin proteins have been found also in healthy individuals, whereas non-myelin antigens have been implicated in neurodegenerative phase of the disease. To provide further putative autoantigens of multiple sclerosis, we investigated the antigen specificity of immunoglobulins present both in sera and in cerebrospinal fluid of patients using phage display technology in a new improved format. A human brain cDNA phage display library was constructed and enriched for open-read-frame fragments. This library was selected against pooled and purified immunoglobulins from cerebrospinal fluid and sera of multiple sclerosis patients. The antigen library was also screened against an antibody scFv library obtained from RNA of B cells purified from the cerebrospinal fluid of two relapsing remitting patients. From all biopanning a complex of 14 antigens were identified; in particular, one of these antigens, corresponding to DDX24 protein, was present in all selections. The ability of more frequently isolated antigens to discriminate between sera from patients with multiple sclerosis or other neurological diseases was investigated. The more promising novel candidate autoantigens were DDX24 and TCERG1. Both are implicated in RNA modification and regulation which can be altered in neurodegenerative processes. Therefore, we propose that they could be a marker of a particular disease activity state.

Disability and Rehabilitation

Multiple Sclerosis and Related Disorders

Multiple sclerosis (Houndmills, Basingstoke, England), Jan 25, 2018

With many options now available, first therapy choice is challenging in multiple sclerosis (MS) a... more With many options now available, first therapy choice is challenging in multiple sclerosis (MS) and depends mainly on neurologist and patient preferences. To identify prognostic factors for early switch after first therapy choice. Newly diagnosed relapsing-remitting MS patients from 24 Italian centers were included. We evaluated the association of baseline demographics, clinical, and magnetic resonance imaging (MRI) data to the switch probability for lack of efficacy or intolerance/safety with a multivariate Cox analysis and estimated switch rates by competing risks models. We enrolled 3025 patients. The overall switch frequency was 48% after 3 years. Switch risk for lack of efficacy was lower with fingolimod (hazard ratio (HR) = 0.50; p = 0.009), natalizumab (HR = 0.13; p < 0.001), dimethyl-fumarate (HR = 0.60; p = 0.037), teriflunomide (HR = 0.21; p = 0.031) as compared to interferons. Younger age (HR = 0.96; p < 0.001), diagnosis delay (HR = 1.23; p = 0.021), higher baselin...

Journal of neurology, 2018

Few studies have evaluated the impact of physical activity (PA) on cognition and fatigue, and non... more Few studies have evaluated the impact of physical activity (PA) on cognition and fatigue, and none have considered the effects of PA on the relationship between cognition and fatigue. We evaluated the effect of PA in people with multiple sclerosis (pwMS) in a 6-month-long single-blind randomized controlled trial. We focused on the impact of exercise on cognition, fatigue, and the relationship between cognition and fatigue. We recruited pwMS, who were then randomly assigned 1:1 to either a PA protocol group or a control group (CG). All patients underwent assessments using the Brief International Cognitive Assessment for Multiple Sclerosis including symbol digit modality test (SDMT), Berg Balance Scale (BBS), gait analysis, 6-Minute Walk Test, Timed Up and Go (TUG) test, and the Modified Fatigue Impact Scale (MFIS) at the beginning of the study (T0), at the end of the study (EOS) 24 weeks after T0, and at 24 weeks following the EOS (FU). A Wilcoxon test revealed a significant effect o...

Journal of neurology, 2018

In this independent, multicenter, retrospective study, we investigated the short-term persistence... more In this independent, multicenter, retrospective study, we investigated the short-term persistence to treatment with first-line self-injectable or oral disease-modifying treatments (DMTs) in patients with relapsing-remitting multiple sclerosis. Data of patients regularly attending 21 Italian MS Centres who started a self-injectable or an oral DMT in 2015 were collected to: (1) estimate the proportion of patients discontinuing the treatment; (3) explore reasons for discontinuation; (3) identify baseline predictors of treatment discontinuation over a follow-up period of 12 months. We analyzed data of 1832 consecutive patients (1289 women, 543 men); 374 (20.4%) of them discontinued the prescribed DMT after a median time of 6 months (range 3 days to 11.5 months) due to poor tolerability (n = 163; 43.6%), disease activity (n = 95; 25.4%), adverse events (n = 64; 17.1%), convenience (i.e. availability of new drug formulations) and pregnancy planning (n = 21; 1.1%). Although the proportion ...

Neurology, Jan 7, 2018

To assess fetal risk after pregnancy exposure to natalizumab in women with multiple sclerosis (MS... more To assess fetal risk after pregnancy exposure to natalizumab in women with multiple sclerosis (MS), with a specific focus on spontaneous abortion (SA) and congenital anomalies (CA). Data of all pregnancies occurring between 2009 and 2015 in patients with MS treated with natalizumab and referring to 19 participating sites were collected and compared with those of pregnancies in untreated patients and patients treated with injectable immunomodulatory agents. Rates of SA and CA were also compared with those reported in the Italian population. Multivariable logistic and linear regression models were performed. A total of 92 pregnancies were tracked in 83 women. In the multivariable analysis, natalizumab exposure was associated with SA (odds ratio [OR] 3.9, 95% confidence interval [CI] 1.9-8.5,< 0.001). However, the rate of SA (17.4%) was within the estimates for the general population, as well as the rate of major CA (3.7%). Moreover, exposure to natalizumab and interferon-β (IFN-β) ...

Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 2018

Drug Design, Development and Therapy

Multiple sclerosis (MS) is a complex disease of the central nervous system that can cause permane... more Multiple sclerosis (MS) is a complex disease of the central nervous system that can cause permanent disability in young adults. A large armamentarium is available for its management and is increasing over time. Ozanimod is an oral drug belonging to the sphingosine-1-phosphate receptor (S1PR) modulator family recently approved in different countries for MS with active disease. It selectively modulates S1PR1 and S1PR5 to prevent autoreactive lymphocytes from entering the central nervous system (CNS), where they can determine inflammation and neurodegeneration. Ozanimod was tested in one Phase II and two Phase III pivotal trials and was shown to be effective and well tolerated. Moreover, further investigations, including comparative trials with other S1P modulators and MS disease-modifying drugs, are needed to better define placement in MS treatment. Furthermore, ozanimod is currently under evaluation for inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease, in international phase III studies. This article retraces the itinerary leading to the approval of ozanimod for MS treatment and its peculiarities and potentiality inside the S1PR modulator family.

European Journal of Neurology

Symmetry

The majority of people with Multiple Sclerosis (pwMS), report lower limb motor dysfunctions, whic... more The majority of people with Multiple Sclerosis (pwMS), report lower limb motor dysfunctions, which may relevantly affect postural control, gait and a wide range of activities of daily living. While it is quite common to observe a different impact of the disease on the two limbs (i.e., one of them is more affected), less clear are the effects of such asymmetry on gait performance. The present retrospective cross-sectional study aimed to characterize the magnitude of interlimb asymmetry in pwMS, particularly as regards the joint kinematics, using parameters derived from angle-angle diagrams. To this end, we analyzed gait patterns of 101 pwMS (55 women, 46 men, mean age 46.3, average Expanded Disability Status Scale (EDSS) score 3.5, range 1–6.5) and 81 unaffected individuals age- and sex-matched who underwent 3D computerized gait analysis carried out using an eight-camera motion capture system. Spatio-temporal parameters and kinematics in the sagittal plane at hip, knee and ankle join...

Frontiers in Neurology

Objectives: The aim of this study was to characterize multiple sclerosis (MS) patients exposed to... more Objectives: The aim of this study was to characterize multiple sclerosis (MS) patients exposed to dimethyl fumarate (DMF) and to evaluate the predictors of therapeutic response. In addition, the study offers a picture of how DMF use has changed over the past few years in naive or switcher patients.Methods: In this observational monocentric study, we examined the prescription flow of DMF in MS patients categorized as naive or switchers (for safety/tolerability, ineffectiveness, and de-escalation strategy) from 2015 to 2019. Clinical and magnetic resonance imaging data of DMF-treated patients were analyzed, and NEDA-3 status at 24 months was evaluated by the three assessment components (absence of clinical relapses, no Expanded Disability Status Scale progression, no radiological activity). Determinants of therapeutic response were also evaluated using regression analysis.Results: The sample included 595 MS patients exposed to DMF categorized as naive (158; 26.5%) and switchers for re...

Background: Approximately 60% of people with multiple sclerosis (PwMS) suffer from upper limb dys... more Background: Approximately 60% of people with multiple sclerosis (PwMS) suffer from upper limb dysfunction. Our primary goal is to implement a single-blind, randomized control trial (RCT) designed to compare the effectiveness of an 8-week home-based telerehab virtual reality (VR) program with conventional therapy in PwMS with manual dexterity difficulties. Secondary aims include: a) evaluating the impact of the programs on quality of life after the intervention and a follow up 1 month later; and b) evaluating the impact of the programs on adherence and satisfaction. Methods: Twenty-four PwMS will be recruited to the study which will be conducted at two established MS centers: (1) The Regional Center for Diagnosis and Treatment of Multiple Sclerosis, Binaghi Hospital, Cagliari, Italy; (2) The Multiple Sclerosis Center, Sheba Medical Center, Tel-Hashomer, Israel. Participants will complete a total of three assessments focusing on upper limb functions. Both groups will receive 16 traini...

International Journal of Environmental Research and Public Health

In people with multiple sclerosis (pwMS), fatigue, weakness and spasticity may reduce mobility an... more In people with multiple sclerosis (pwMS), fatigue, weakness and spasticity may reduce mobility and promote sedentary behavior. However, little is known about the existence of possible differences in the way MS modifies the propensity to perform physical activity (PA) in men and women. The present study aimed to partly close this gap by means of quantitative analysis carried out using wearable sensors. Forty-five pwMS (23 F, 22 M, mean age 50.3) and 41 unaffected age- and sex-matched individuals wore a tri-axial accelerometer 24 h/day for 7 consecutive days. Raw data were processed to calculate average number of daily steps, vector magnitude (VM) counts, and percentage of time spent in sedentary behavior and in PA of different intensities (i.e., light and moderate-to-vigorous, MVPA). Women with MS spent more time in sedentary behavior and exhibited a reduced amount of light intensity activity with respect to men, while MVPA was similar across sexes. However, in comparison with unaffe...

Multiple Sclerosis and Related Disorders

Microorganisms

Interleukin 2 (IL-2) is considered a key player in exacerbating multiple sclerosis (MS). Therapie... more Interleukin 2 (IL-2) is considered a key player in exacerbating multiple sclerosis (MS). Therapies targeting its receptor have been developed; however, a resolution of the disease and side effects are still an issue of concern. The involvement of other factors, such as Mycobacterium avium subspecies paratuberculosis (MAP) and envelope protein derived from human endogenous retrovirus type W (HERV-Wenv), in MS pathogenesis has been recently suggested. Here, we investigated the levels of antibodies (Abs) directed against IL-2 and HERV-Wenv in 108 MS patients, 34 patients affected by neuromyelitis optica spectrum disorder (NMOSD), and 137 healthy controls (HCs). Our results show increased levels of Abs specific to IL-2 and HERV-Wenv-su antigens in MS vs. HCs (p < 0.0001 for IL-2, p = 0.0004 for HERV-Wenv) and significantly decreased levels in NMOSD vs. MS. The assessment of different 12-month-long therapies on Abs against IL-2, HERV-Wenv, and MAP lipoarabinomannan (LAM) demonstrated ...

PLOS ONE

Although the etiology of multiple sclerosis is not yet understood, it is accepted that its pathog... more Although the etiology of multiple sclerosis is not yet understood, it is accepted that its pathogenesis involves both autoimmune and neurodegenerative processes, in which the role of autoreactive T-cells has been elucidated. Instead, the contribution of humoral response is still unclear, even if the presence of intrathecal antibodies and B-cells follicle-like structures in meninges of patients has been demonstrated. Several myelin and non-myelin antigens have been identified, but none has been validated as humoral biomarker. In particular autoantibodies against myelin proteins have been found also in healthy individuals, whereas non-myelin antigens have been implicated in neurodegenerative phase of the disease. To provide further putative autoantigens of multiple sclerosis, we investigated the antigen specificity of immunoglobulins present both in sera and in cerebrospinal fluid of patients using phage display technology in a new improved format. A human brain cDNA phage display library was constructed and enriched for open-read-frame fragments. This library was selected against pooled and purified immunoglobulins from cerebrospinal fluid and sera of multiple sclerosis patients. The antigen library was also screened against an antibody scFv library obtained from RNA of B cells purified from the cerebrospinal fluid of two relapsing remitting patients. From all biopanning a complex of 14 antigens were identified; in particular, one of these antigens, corresponding to DDX24 protein, was present in all selections. The ability of more frequently isolated antigens to discriminate between sera from patients with multiple sclerosis or other neurological diseases was investigated. The more promising novel candidate autoantigens were DDX24 and TCERG1. Both are implicated in RNA modification and regulation which can be altered in neurodegenerative processes. Therefore, we propose that they could be a marker of a particular disease activity state.

Disability and Rehabilitation

Multiple Sclerosis and Related Disorders

Multiple sclerosis (Houndmills, Basingstoke, England), Jan 25, 2018

With many options now available, first therapy choice is challenging in multiple sclerosis (MS) a... more With many options now available, first therapy choice is challenging in multiple sclerosis (MS) and depends mainly on neurologist and patient preferences. To identify prognostic factors for early switch after first therapy choice. Newly diagnosed relapsing-remitting MS patients from 24 Italian centers were included. We evaluated the association of baseline demographics, clinical, and magnetic resonance imaging (MRI) data to the switch probability for lack of efficacy or intolerance/safety with a multivariate Cox analysis and estimated switch rates by competing risks models. We enrolled 3025 patients. The overall switch frequency was 48% after 3 years. Switch risk for lack of efficacy was lower with fingolimod (hazard ratio (HR) = 0.50; p = 0.009), natalizumab (HR = 0.13; p < 0.001), dimethyl-fumarate (HR = 0.60; p = 0.037), teriflunomide (HR = 0.21; p = 0.031) as compared to interferons. Younger age (HR = 0.96; p < 0.001), diagnosis delay (HR = 1.23; p = 0.021), higher baselin...

Journal of neurology, 2018

Few studies have evaluated the impact of physical activity (PA) on cognition and fatigue, and non... more Few studies have evaluated the impact of physical activity (PA) on cognition and fatigue, and none have considered the effects of PA on the relationship between cognition and fatigue. We evaluated the effect of PA in people with multiple sclerosis (pwMS) in a 6-month-long single-blind randomized controlled trial. We focused on the impact of exercise on cognition, fatigue, and the relationship between cognition and fatigue. We recruited pwMS, who were then randomly assigned 1:1 to either a PA protocol group or a control group (CG). All patients underwent assessments using the Brief International Cognitive Assessment for Multiple Sclerosis including symbol digit modality test (SDMT), Berg Balance Scale (BBS), gait analysis, 6-Minute Walk Test, Timed Up and Go (TUG) test, and the Modified Fatigue Impact Scale (MFIS) at the beginning of the study (T0), at the end of the study (EOS) 24 weeks after T0, and at 24 weeks following the EOS (FU). A Wilcoxon test revealed a significant effect o...

Journal of neurology, 2018

In this independent, multicenter, retrospective study, we investigated the short-term persistence... more In this independent, multicenter, retrospective study, we investigated the short-term persistence to treatment with first-line self-injectable or oral disease-modifying treatments (DMTs) in patients with relapsing-remitting multiple sclerosis. Data of patients regularly attending 21 Italian MS Centres who started a self-injectable or an oral DMT in 2015 were collected to: (1) estimate the proportion of patients discontinuing the treatment; (3) explore reasons for discontinuation; (3) identify baseline predictors of treatment discontinuation over a follow-up period of 12 months. We analyzed data of 1832 consecutive patients (1289 women, 543 men); 374 (20.4%) of them discontinued the prescribed DMT after a median time of 6 months (range 3 days to 11.5 months) due to poor tolerability (n = 163; 43.6%), disease activity (n = 95; 25.4%), adverse events (n = 64; 17.1%), convenience (i.e. availability of new drug formulations) and pregnancy planning (n = 21; 1.1%). Although the proportion ...

Neurology, Jan 7, 2018

To assess fetal risk after pregnancy exposure to natalizumab in women with multiple sclerosis (MS... more To assess fetal risk after pregnancy exposure to natalizumab in women with multiple sclerosis (MS), with a specific focus on spontaneous abortion (SA) and congenital anomalies (CA). Data of all pregnancies occurring between 2009 and 2015 in patients with MS treated with natalizumab and referring to 19 participating sites were collected and compared with those of pregnancies in untreated patients and patients treated with injectable immunomodulatory agents. Rates of SA and CA were also compared with those reported in the Italian population. Multivariable logistic and linear regression models were performed. A total of 92 pregnancies were tracked in 83 women. In the multivariable analysis, natalizumab exposure was associated with SA (odds ratio [OR] 3.9, 95% confidence interval [CI] 1.9-8.5,< 0.001). However, the rate of SA (17.4%) was within the estimates for the general population, as well as the rate of major CA (3.7%). Moreover, exposure to natalizumab and interferon-β (IFN-β) ...

Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 2018