Adiponectin exerts relevant actions in immunity and is modulated in several disorders, such as multiple sclerosis (MS). In this study, we characterized adiponectin expression and profiles in ...cerebrospinal fluid (CSF) from MS patients to investigate its potential relationship with the severity and progression of the disease. Total adiponectin in CSF was measured by ELISA in 66 unrelated CSF MS patients and compared with 24 age- and sex-matched controls. Adiponectin oligomer profiles were analysed by Western blotting and FPLC chromatography. Total CSF adiponectin was significantly increased in MS patients compared with controls (9.91 ng/mL vs 6.02 ng/mL) (
p
< 0.001). Interestingly, CSF adiponectin positively correlated with CSF IgG, and CSF/serum albumin directly correlated with CSF/serum adiponectin. Our data demonstrated that CSF adiponectin predicts a worse prognosis: patients with the progressive form of MS had higher levels compared with the relapsing remitting form; patients with higher EDSS at baseline and a higher MS severity score at 4.5-year follow-up had significantly elevated adiponectin levels with respect to patients with a less severe phenotype. Finally, the adiponectin oligomerization profile was altered in CSF from MS patients, with a significant increase in HMW and MMW. The correlation of CSF adiponectin with the severity and prognosis of MS disease confirmed the role of this adipokine in the inflammatory/immune processes of MS and suggested its use as a complementary tool to assess the severity, progression and prognosis of the disease. Further studies on larger MS cohorts are needed to clarify the contribution of adiponectin to the etiopathogenesis of MS.
Hepatitis C virus(HCV)infection is considered a systemic disease because of involvement of other organs and tissues concomitantly with liver disease.Among the extrahepatic ...manifestations,neuropsychiatric disorders have been reported in up to 50%of chronic HCV infected patients.Both the central and peripheral nervous system may be involved with a wide variety of clinical manifestations.Main HCV-associated neurological conditions include cerebrovascular events,encephalopathy,myelitis,encephalomyelitis,and cognitive impairment,whereas"brain fog",depression,anxiety,and fatigue are at the top of the list of psychiatric disorders.Moreover,HCV infection is known to cause both motor and sensory peripheral neuropathy in the context of mixed cryoglobulinemia,and has also been recently recognized as an independent risk factor for stroke.These extrahepatic manifestations are independent of severity of the underlying chronic liver disease and hepatic encephalopathy.The brain is a suitable site for HCV replication,where the virus may directly exert neurotoxicity;other mechanisms proposed to explain the pathogenesis of neuropsychiatric disorders in chronic HCV infection include derangement of metabolic pathways of infected cells,alterations in neurotransmitter circuits,autoimmune disorders,and cerebral or systemic inflammation.A pathogenic role for HCV is also suggested by improvement of neurological and psychiatric symptoms in patients achieving a sustained virologic response following interferon treatment;however,further ad hoc trials are needed to fully assess the impact of HCV infection and specific antiviral treatments on associated neuropsychiatric disorders.
Background:
The COVID-19 pandemic has underlined the need to evaluate cognitive profile via videoconferencing (teleneuropsychology, TeleNP) as a suitable alternative to face-to-face assessment (F-F).
...Objective:
To evaluate the feasibility and the reliability of Rao’s Brief Repeatable Battery of Neuropsychological Tests (R-BRB) remote administration in people with multiple sclerosis (PwMS).
Methods:
Sixty PwMS underwent R-BRB in two conditions: F-F and TeleNP, 1 month apart.
Results:
Cognitive test performance was similar, regardless of the administration type, but visuospatial test performance was better in F-F.
Conclusion:
These data suggest that TeleNP is feasible and highly reliable in MS clinical practice.
Extending the natalizumab interval after the 24th administration could reduce the risk of progressive multifocal leukoencephalopathy (PML). The objective is to evaluate the noninferiority of the ...efficacy of an extended interval dosing (EID) compared with the standard interval dosing (SID) of natalizumab. It is an observational, multicenter (14 Italian centers), retrospective cohort study, starting from the 24th natalizumab infusion to the loss of follow-up or 2 years after baseline. Patients were grouped in 2 categories according to the mean number of weeks between doses: < 5 weeks, SID; ≥ 5 weeks, EID. Three hundred and sixty patients were enrolled. Median dose interval (MDI) following 24th infusion was 4.7 weeks, with a bimodal distribution (modes at 4 and 6 weeks). Two hundred and sixteen patients were in the SID group (MDI = 4.3 weeks) and 144 in the EID group (MDI 6.2 weeks). Annualized relapse rate was 0.060 (95% CI = 0.033–0.087) in the SID group and 0.039 (95% CI = 0.017–0.063) in the EID group. The non-inferiority of EID
versus
SID was satisfied. In conclusion, there is no evidence of a reduced efficacy of natalizumab in an EID setting. This observation confirms previous results and together with the emerging evidence of a reduced risk of PML associated to an EID, supports the need of a randomized study to assess the need to change the standard of the natalizumab dosing schedule.
The main aim of the study is to evaluate the efficacy and safety profile of ocrelizumab (OCR), rituximab (RTX), and cladribine (CLA), employed as natalizumab (NTZ) exit strategies in ...relapsing–remitting multiple sclerosis (RRMS) patients at high-risk for progressive multifocal leukoencephalopathy (PML). This is a multicentre, retrospective, real-world study on consecutive RRMS patients from eleven tertiary Italian MS centres, who switched from NTZ to OCR, RTX, and CLA from January 1st, 2019, to December 31st, 2019. The primary study outcomes were the annualized relapse rate (ARR) and magnetic resonance imaging (MRI) outcome. Treatment effects were estimated by the inverse probability treatment weighting (IPTW), based on propensity-score (PS) approach. Additional endpoint included confirmed disability progression (CDP) as measured by Expanded Disability Status Scale and adverse events (AEs). Patients satisfying predefined inclusion and exclusion criteria were 120; 64 switched to OCR, 36 to RTX, and 20 to CLA. Patients from the 3 groups did not show differences for baseline characteristics, also after post hoc analysis. The IPTW PS-adjusted models revealed that patients on OCR had a lower risk for ARR than patients on CLA (ExpB
OCR
0.485, CI 95% 0.264–0.893,
p
= 0.020). This result was confirmed also for 12-month MRI activity (ExpB
OCR
0.248 CI 95% 0.065–0.948,
p
= 0.042). No differences were found in other pairwise comparisons (OCR vs RTX and RTX vs CLA) for the investigated outcomes. AEs were similar among the 3 groups. Anti-CD20 drugs were revealed to be effective and safe options as NTZ exit strategies. All investigated DMTs showed a good safety profile.
Objectives:
Switching between treatments is an opportunity for patients with multiple sclerosis (MS) to ameliorate disease control or safety. The aim of this study was to investigate the impact of ...switching from fingolimod (FTY) or natalizumab (NTZ) to ocrelizumab (OCR) on disease activity.
Methods:
We retrospectively enrolled 165 patients treated with OCR from 11 MS centres. We assessed the association of demographic and clinical characteristics on relapse rate (RR) and activity on magnetic resonance imaging (MRI) during wash-out and after 6 months of treatment with OCR through univariable and multivariable negative binomial regression models.
Results:
We registered a total of 35 relapses during the wash-out period. Previous treatment with FTY, relapses in the previous year, and relapsing-remitting course were associated with higher RR. In the first 6 months of OCR, 12 patients had clinical or MRI disease activity. Higher Expanded Disability Status Scale (EDSS) and higher lymphocyte count at OCR start were associated with a reduced probability of relapse.
Discussion and Conclusion:
This study confirms that withdrawal from sequestering agents as FTY increases the risk of relapses in the wash-out period. Nevertheless, starting OCR before achieving complete immune reconstitution could limit its effectiveness in the first 6 months probably because trapped lymphocytes escape the CD20-mediated depletion.
Multiple sclerosis (MS) requires multidisciplinary management. We evaluated differences in healthcare resource utilization and costs between Federico II and Vanvitelli MS Centres of Naples (Italy), ...representative of centralised (i.e., MS Care Unit) and local service-based models of multidisciplinary care, respectively.
We included MS patients continuously seen at the same local healthcare services and MS Centre (Federico II = 187; Vanvitelli = 90) from 2015 to 2017. Healthcare resources for MS treatment and management were collected and costs were calculated. Adherence was estimated as the rate of medication possession ratio (MPR) during 3-years of follow-up. Mixed-effect linear regression models were used to estimate differences in all outcomes between Federico II and Vanvitelli.
Patients at Federico II had more consultations within the MS centre (p<0.001), blood tests (p<0.001), and psychological/cognitive evaluations (p = 0.040). Patients at Vanvitelli had more consultations at local services (p<0.001). Adherence was not-significantly lower at Vanvitelli (p = 0.060), compared with Federico II. Costs for MS treatment and management were 10.6% lower at Vanvitelli (12417.08±8448.32EUR) (95%CI = -19.0/-2.7%;p = 0.007), compared with Federico II (15318.57±10919.59EUR).
Healthcare services were more complete (and expensive) at the Federico II centralised MS Care Unit, compared with the Vanvitelli local service-based organizational model. Future research should evaluate whether better integration between MS Centres and local services can lead to improved MS management and lower costs.
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 (n = 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 (n = 2343, 12.1%) were older, more disabled and with a faster progression to severe disability (p < 0.0001), than those identified by the ND (n = 3868, 20.0%). In both groups, the most consistent risk factors (p < 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.
Background and aims:
No consensus exists on how aggressively to treat relapsing–remitting multiple sclerosis (RRMS) nor on the timing of the treatment. The objective of this study was to evaluate ...disability trajectories in RRMS patients treated with an early intensive treatment (EIT) or with a moderate-efficacy treatment followed by escalation to higher-efficacy disease modifying therapy (ESC).
Methods:
RRMS patients with ⩾5-year follow-up and ⩾3 visits after disease modifying therapy (DMT) start were selected from the Italian MS Registry. EIT group included patients who received as first DMT fingolimod, natalizumab, mitoxantrone, alemtuzumab, ocrelizumab, cladribine. ESC group patients received the high efficacy DMT after ⩾1 year of glatiramer acetate, interferons, azathioprine, teriflunomide or dimethylfumarate treatment. Patients were 1:1 propensity score (PS) matched for characteristics at the first DMT. The disability trajectories were evaluated by applying a longitudinal model for repeated measures. The effect of early versus late start of high-efficacy DMT was assessed by the mean annual Expanded Disability Status Scale (EDSS) changes compared with baseline values (delta-EDSS) in EIT and ESC groups.
Results:
The study cohort included 2702 RRMS patients. The PS matching procedure produced 363 pairs, followed for a median (interquartile range) of 8.5 (6.5–11.7) years. Mean annual delta-EDSS values were all significantly (p < 0.02) higher in the ESC group compared with the EIT group. In particular, the mean delta-EDSS differences between the two groups tended to increase from 0.1 (0.01–0.19, p = 0.03) at 1 year to 0.30 (0.07–0.53, p = 0.009) at 5 years and to 0.67 (0.31–1.03, p = 0.0003) at 10 years.
Conclusion:
Our results indicate that EIT strategy is more effective than ESC strategy in controlling disability progression over time.
Multiple sclerosis (MS) is the most common disabling neurological disease characterized by chronic inflammation and neuronal cell viability impairment. Based on previous studies reporting that ...adiponectin exhibits neuroprotective effects in some models of neurodegenerative diseases, we analyzed the effects of AdipoRon treatment, alone or in combination with the cerebrospinal fluid of patients with MS (MS-CSF), to verify whether this adipokine acts on the basal neuronal cellular processes. To this aim, SH-SY5Y and U-87 cells (models of neuronal and glial cells, respectively) were exposed to MS-CSF alone or in co-treatment with AdipoRon. The cell viability was determined via MTT assay, and the possible underlying mechanisms were investigated via the alterations of oxidative stress and inflammation. MTT assay confirmed that AdipoRon alone did not affect the viability of both cell lines; whereas, when used in combination with MS-CSF, it reduces MS-CSF inhibitory effects on the viability of both SH-SY5Y and U-87 cell lines. In addition, MS-CSF treatment causes an increase in pro-inflammatory cytokines, whereas it determines the reduction in anti-inflammatory IL-10. Interestingly, the co-administration of AdipoRon counteracts the MS-CSF-induced production of pro-inflammatory cytokines, whereas it determines an enhancement of IL-10. In conclusion, our data suggest that AdipoRon counteracts the cytotoxic effects induced by MS-CSF on SH-SY5Y and U-87 cell lines and that one of the potential molecular underlying mechanisms might occur via reduction in oxidative stress and inflammation. Further in vivo and in vitro studies are essential to confirm whether adiponectin could be a neuro-protectant candidate against neuronal cell injury.
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