Ocrelizumab and ofatumumab comparison: an Italian real-world propensity score matched study.

BACKGROUND: The management of Multiple Sclerosis (MS) has undergone transformative evolution with the introduction of high-efficacy disease-modifying therapies (DMTs), specifically anti-CD20 monoclonal antibodies, such as ocrelizumab (OCR) and ofatumumab (OFA). MATERIALS AND METHODS: This is an independent retrospective cohort study in Relapsing MS (RMS) patients followed at eight Italian MS centers who initiated treatment with OCR or OFA in the participating centers and with at least 12 months on therapy. A generalized linear regression model inverse probability of treatment weight (IPTW) PS-adjusted was performed to evaluate the relationship between annualized relapse rate (ARR) and treatment groups. No evidence of disease activity-NEDA-3 at 12-month score was also collected. Safety profile of the investigated DMTs was recorded. RESULTS: A total cohort of 396 RMS patients fulfilled the required criteria and were enrolled in the study. Out of them, 216 had a prescription of OCR and 180 of OFA. The mean follow-up was 13.2 ± 1.9 months. The estimated means for ARR did not show differences between the two groups, 0.059 for patients on OCR and 0.038 for patients on OFA (p = 0.185). The generalized regression model IPTW PS-adjusted did not reveal differences between patients on OCR and OFA (ExpBOFA 0.974, 95%CI 934-1.015, p = 0.207). NEDA-3 at 12 months was experienced by 199(92.1%) patients on OCR and 170(94.4%) patients on OFA (p = 0.368). Generally, both therapies exhibit good tolerability. CONCLUSIONS: The treatment with OCR and OFA resulted in comparable control of disease activity with good safety profile. Our results need further validation in larger multicentre studies with long-term follow-up.

Progression independent of relapse activity in relapsing multiple sclerosis: impact and relationship with secondary progression.

OBJECTIVES: We investigated the occurrence and relative contribution of relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA) to confirmed disability accrual (CDA) and transition to secondary progression (SP) in relapsing multiple sclerosis (MS). METHODS: Relapsing-onset MS patients with follow-up > / = 5 years (16,130) were extracted from the Italian MS Registry. CDA was a 6-month confirmed increase in Expanded Disability Status Scale (EDSS) score. Sustained disability accumulation (SDA) was a CDA with no EDSS improvement in all subsequent visits. Predictors of PIRA and RAW and the association between final EDSS score and type of CDA were assessed using logistic multivariable regression and multivariable ordinal regression models, respectively. RESULTS: Over 11.8 ± 5.4 years, 16,731 CDA events occurred in 8998 (55.8%) patients. PIRA (12,175) accounted for 72.3% of CDA. SDA occurred in 8912 (73.2%) PIRA and 2583 (56.7%) RAW (p < 0.001). 4453 (27.6%) patients transitioned to SPMS, 4010 (73.2%) out of 5476 patients with sustained PIRA and 443 (24.8%) out of 1790 patients with non-sustained PIRA. In the multivariable ordinal regression analysis, higher final EDSS score was associated with PIRA (estimated coefficient 0.349, 95% CI 0.120-0.577, p = 0.003). DISCUSSION: In this real-world relapsing-onset MS cohort, PIRA was the main driver of disability accumulation and was associated with higher disability in the long term. Sustained PIRA was linked to transition to SP and could represent a more accurate PIRA definition and a criterion to mark the putative onset of the progressive phase.

Idiopathic generalized epilepsy in a family with SCN4A-related myotonia.

OBJECTIVES: Myotonia is a clinical sign typical of a group of skeletal muscle channelopathies, the non-dystrophic myotonias. These disorders are electrophysiologically characterized by altered membrane excitability, due to specific genetic variants in known causative genes (CLCN1 and SCN4A). Juvenile Myoclonic Epilepsy (JME) is an epileptic syndrome identified as idiopathic generalized epilepsy, its genetics is complex and still unclarified. The co-occurrence of these two phenotypes is rare and the causes likely have a genetic background. In this study, we have genetically investigated an Italian family in which co-segregates myotonia, JME, or abnormal EEG without seizures was observed. METHODS: All six individuals of the family, 4 affected and 2 unaffected, were clinically evaluated; EMG and EEG examinations were performed. For genetic testing, Exome Sequencing was performed for the six family members and Sanger sequencing was used to confirm the candidate variant. RESULTS: Four family members, the mother and three siblings, were affected by myotonia. Moreover, EEG recordings revealed interictal generalized sharp-wave discharges in all affected individuals, and two siblings were affected by JME. All four affected members share the same identified variant, c.644 T > C, p.Ile215Thr, in SCN4A gene. Variants that could account for the epileptic phenotype alone, separately from the myotonic one, were not identified. SIGNIFICANCE: These results provide supporting evidence that both myotonic and epileptic phenotypes could share a common genetic background, due to variants in SCN4A gene. SCN4A pathogenic variants, already known to be causative of myotonia, likely increase the susceptibility to epilepsy in our family. PLAIN LANGUAGE SUMMARY: This study analyzed all members of an Italian family, in which the mother and three siblings had myotonia and epilepsy. Genetic analysis allowed to identify a variant in the SCN4A gene, which appears to be the cause of both clinical signs in this family.

Identifying definite patterns of unmet needs in patients with multiple sclerosis using unsupervised machine learning.

INTRODUCTION: People with multiple sclerosis (PwMS) exhibit a spectrum of needs that extend beyond solely disease-related determinants. Investigating unmet needs from the patient perspective may address daily difficulties and optimize care. Our aim was to identify patterns of unmet needs among PwMS and their determinants. METHODS: We conducted a cross-sectional multicentre study. Data were collected through an anonymous, self-administered online form. To cluster PwMS according to their main unmet needs, we performed agglomerative hierarchical clustering algorithm. Principal component analysis (PCA) was applied to visualize cluster distribution. Pairwise comparisons were used to evaluate demographics and clinical distribution among clusters. RESULTS: Out of 1764 mailed questionnaires, we received 690 responses. Access to primary care was the main contributor to the overall unmet need burden. Four patterns were identified: cluster C1, 'information-seekers with few unmet needs'; cluster C2, 'high unmet needs'; cluster C3, 'socially and assistance-dependent'; cluster C4, 'self-sufficient with few unmet needs'. PCA identified two main components in determining the patterns: the 'public sphere' (access to information and care) and the 'private sphere' (need for assistance and social life). Older age, lower education, longer disease duration and higher disability characterized clusters with more unmet needs in the private sphere. However, demographic and clinical factors failed in explaining the four identified patterns. CONCLUSION: Our study identified four unmet need patterns among PwMS, emphasizing the importance of personalized care. While clinical and demographic factors provide some insight, additional variables warrant further investigation to fully understand unmet needs in PwMS.

Humoral and T-cell response to SARS-CoV-2 mRNA vaccine in multiple sclerosis patients: Correlations with DMTs and clinical variables.

Disease-modifying therapies (DMTs) can affect vaccine responses in individuals with multiple sclerosis (MS). We assessed the humoral and T-cell responses following SARS-CoV-2 mRNA vaccination in MS patients receiving various DMTs. We prospectively enrolled 243 participants, including 113 healthy control subjects and 130 MS patients. Blood samples for detecting SARS-CoV-2 antibodies were collected at three time points: T0, before the first vaccine dose; T1, before the second dose; and T2, one month after the second dose. In a subgroup of 51 patients and 20 controls, samples were collected at T0 and T2 to assess the T-cell immune response to the Spike antigen of SARS-CoV-2 using ELISPOT-IFNγ. The IgG levels in patients treated with fingolimod and ocrelizumab (159.1 AU/ml and 467.1 AU/ml, respectively) were significantly lower than those in healthy controls and patients on other DMTs (P â€‹< â€‹0.0001). The mean Ig titers were higher in patients with an absolute lymphocyte count ≥1000 â€‹cells/mm3 compared to those with a count between 500 and 1000 and with a count <500 (mean â€‹± â€‹SD:7205.6 â€‹± â€‹7339.2, 2413.1 â€‹± â€‹4515.4 and 165.9 â€‹± â€‹152.2, respectively; p â€‹= â€‹0.008). We found correlations between antibody levels and age (r â€‹= â€‹0.233, p â€‹= â€‹0.008). A positive Spike-specific T-cell response was detectable in 100 â€‹% of vaccinated healthy controls and patients treated with teriflunomide, dimethyl-fumarate, and natalizumab, in 90.5 â€‹% of fingolimod patients, and in 63.8 â€‹% of ocrelizumab patients. There is a correlation between IgG-specific titer after SARS-CoV-2 vaccination and clinical variables (age, lymphocyte count). Notably, a T-cell-specific response to SARS-CoV-2 developed in patients treated with fingolimod and ocrelizumab, even with lower rates of humoral response.

Ocrelizumab Extended Interval Dosing in Primary Progressive Multiple Sclerosis: An Italian Experience.

BACKGROUND: The intervals between two courses of anti CD20 therapies in the COVID19 pandemic era provided the opportunity to individually delay therapy, known as extended interval dosing (EID). METHODS: We collect real-world data on patients with primary progressive MS (PPMS) treated with Ocrelizumab (OCR) during the COVID'19 pandemic. The observation period in which the standard interval dosing (SID) or EID occurred (always a maintenance cycle, 600 mg) was from January 2020 to June 2021. All patients had two infusions during the observation period. Our first aim was to compare confirmed disability progression (CDP) between SID and EID patients. RESULTS: From a total cohort of 410 patients treated with OCR, 96 patients fulfilled the inclusion criteria. All patients received two infusions during the index window, 71 received only SID infusions whilst 25 received at least one EID infusion throughout the entire follow-up. During the entire available follow-up (median 10 months, IQR 7-11), CDP was recorded in 5 patients (3/71, 4.2% SID and 2/25, 8% EID, V-Cramer = 0.141, p-value = 0.167). EID regimen did not influence the risk of CDP during the investigated follow up. CONCLUSION: In our multicentre real-world cohort, the EID regimen in PPMS patients did not result in increased CDP during the available follow-up.

Multiple Sclerosis Progression and Relapse Activity in Children.

Importance: Although up to 20% of patients with multiple sclerosis (MS) experience onset before 18 years of age, it has been suggested that people with pediatric-onset MS (POMS) are protected against disability because of greater capacity for repair. Objective: To assess the incidence of and factors associated with progression independent of relapse activity (PIRA) and relapse-associated worsening (RAW) in POMS compared with typical adult-onset MS (AOMS) and late-onset MS (LOMS). Design, Setting, and Participants: This cohort study on prospectively acquired data from the Italian MS Register was performed from June 1, 2000, to September 30, 2021. At the time of data extraction, longitudinal data from 73 564 patients from 120 MS centers were available in the register. Main Outcomes and Measures: The main outcomes included age-related cumulative incidence and adjusted hazard ratios (HRs) for PIRA and RAW and associated factors. Exposures: Clinical and magnetic resonance imaging features, time receiving disease-modifying therapy (DMT), and time to first DMT. Results: After applying the inclusion and exclusion criteria, the study assessed 16 130 patients with MS (median [IQR] age at onset, 28.7 [22.8-36.2 years]; 68.3% female). Compared with AOMS and LOMS, patients with POMS had less disability, exhibited more active disease, and were exposed to DMT for a longer period. A first 48-week-confirmed PIRA occurred in 7176 patients (44.5%): 558 patients with POMS (40.4%), 6258 patients with AOMS (44.3%), and 360 patients with LOMS (56.8%) (P < .001). Factors associated with PIRA were older age at onset (AOMS vs POMS HR, 1.42; 95% CI, 1.30-1.55; LOMS vs POMS HR, 2.98; 95% CI, 2.60-3.41; P < .001), longer disease duration (HR, 1.04; 95% CI, 1.04-1.05; P < .001), and shorter DMT exposure (HR, 0.69; 95% CI, 0.64-0.74; P < .001). The incidence of PIRA was 1.3% at 20 years of age, but it rapidly increased approximately 7 times between 21 and 30 years of age (9.0%) and nearly doubled for each age decade from 40 to 70 years (21.6% at 40 years, 39.0% at 50 years, 61.0% at 60 years, and 78.7% at 70 years). The cumulative incidence of RAW events followed a similar trend from 20 to 60 years (0.5% at 20 years, 3.5% at 30 years, 7.8% at 40 years, 14.4% at 50 years, and 24.1% at 60 years); no further increase was found at 70 years (27.7%). Delayed DMT initiation was associated with higher risk of PIRA (HR, 1.16; 95% CI, 1.00-1.34; P = .04) and RAW (HR, 1.75; 95% CI, 1.28-2.39; P = .001). Conclusions and Relevance: PIRA can occur at any age, and although pediatric onset is not fully protective against progression, this study's findings suggest that patients with pediatric onset are less likely to exhibit PIRA over a decade of follow-up. However, these data also reinforce the benefit for DMT initiation in patients with POMS, as treatment was associated with reduced occurrence of both PIRA and RAW regardless of age at onset.

Use, tolerability, benefits and side effects of orthotic devices in Charcot-Marie-Tooth disease.

BACKGROUND: Shoe inserts, orthopaedic shoes, ankle-foot orthoses (AFOs) are important devices in Charcot-Marie-Tooth disease (CMT) management, but data about use, benefits and tolerance are scanty. METHODS: We administered to Italian CMT Registry patients an online ad hoc questionnaire investigating use, complications and perceived benefit/tolerability/emotional distress of shoe inserts, orthopaedic shoes, AFOs and other orthoses/aids. Patients were also asked to fill in the Quebec User Evaluation of Satisfaction with assistive Technology questionnaire, rating satisfaction with currently used AFO and related services. RESULTS: We analysed answers from 266 CMT patients. Seventy per cent of subjects were prescribed lower limb orthoses, but 19% did not used them. Overall, 39% of subjects wore shoe inserts, 18% orthopaedic shoes and 23% AFOs. Frequency of abandonment was high: 24% for shoe inserts, 28% for orthopaedic shoes and 31% for AFOs. Complications were reported by 59% of patients and were more frequently related to AFOs (69%). AFO users experienced greater emotional distress and reduced tolerability as compared with shoe inserts (p<0.001) and orthopaedic shoes (p=0.003 and p=0.045, respectively). Disease severity, degree of foot weakness, customisation and timing for customisation were determinant factors in AFOs' tolerability. Quality of professional and follow-up services were perceived issues. CONCLUSIONS: The majority of CMT patients is prescribed shoe inserts, orthopaedic shoes and/or AFOs. Although perceived benefits and tolerability are rather good, there is a high rate of complications, potentially inappropriate prescriptions and considerable emotional distress, which reduce the use of AFOs. A rational, patient-oriented and multidisciplinary approach to orthoses prescription must be encouraged.

Evaluation of drivers of treatment switch in relapsing multiple sclerosis: a study from the Italian MS Registry.

BACKGROUND: Active relapsing-remitting (RR) and secondary progressive (SP) multiple sclerosis (MS) are currently defined as "relapsing MS" (RMS). The aim of this cross-sectional study was to assess drivers of treatment switches due to clinical relapses in a population of RMS patients collected in the Italian MS and Related Disorders Register (I-MS&RD). METHODS: RRMS and SPMS patients with at least one relapse in a time window of 2 years before of data extraction were defined as RMS. Factors associated with disease-modifying therapy (DMT) switching due to clinical activity were assessed through multivariable logistic regression models in which treatment exposure was included as the last recorded DMT and the last DMT's class [moderate-efficacy (ME), high-efficacy (HE) DMTs and anti-CD20 drugs]. RESULTS: A cohort of 4739 RMS patients (4161 RRMS, 578 SPMS) was extracted from the I-MS&RD. A total of 2694 patients switching DMTs due to relapses were identified. Switchers were significantly (p < 0.0001) younger, less disabled, more frequently affected by an RR disease course in comparison to non-switcher patients. The multivariable logistic regression models showed that Alemtuzumab (OR 0.08, 95% CI 0.02-0.37), Natalizumab (0.48, 0.30-0.76), Ocrelizumab (0.1, 0.02-0.45) and Rituximab (0.23, 0.06-0.82) exposure was a protective factor against treatment switch due to relapses. Moreover, the use of HE DMTs (0.43, 0.31-0.59), especially anti-CD20 drugs (0.14, 0.05-0.37), resulted to be a protective factor against treatment switch due to relapses in comparison with ME DMTs. CONCLUSIONS: More than 50% of RMS switched therapy due to disease activity. HE DMTs, especially anti-CD20 drugs, significantly reduce the risk of treatment switch.

Serum Biomarker Profiles Discriminate AQP4 Seropositive and Double Seronegative Neuromyelitis Optica Spectrum Disorder.

BACKGROUND AND OBJECTIVES: Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) serum levels are useful to define disease activity in different neurologic conditions. These biomarkers are increased in patients with aquaporin-4 antibody-positive NMOSD (AQP4+NMOSD) during clinical attacks suggesting a concomitant axonal and glial damage. However, there are contradictory results in double seronegative NMOSD (DS-NMOSD). The aim of this study was to characterize the neuronal, axonal, and glial damage of DS-NMOSD in comparison with AQP4+NMOSD. METHODS: Patients with DS-NMOSD (i.e., for AQP4 and myelin oligodendrocyte glycoprotein antibodies-MOG-Abs) and age-matched AQP4+NMOSD diagnosed according to the latest diagnostic criteria and with available serum samples obtained within 3 months from onset/relapse were retrospectively enrolled from 14 international centers. Clinical and radiologic data were collected. Serum NfL, GFAP, tau, and UCH-L1 levels were determined using an ultrasensitive paramagnetic bead-based ELISA (SIMOA). Statistical analysis was performed using nonparametric tests and receiver-operating characteristic (ROC) curve analysis. RESULTS: We included 25 patients with AQP4+NMOSD and 26 with DS-NMOSD. The median age at disease onset (p = 0.611) and female sex predominance (p = 0.072) were similar in the 2 groups. The most common syndromes at sampling in both AQP4+NMOSD and DS-NMOSD were myelitis (56% vs 38.5%) and optic neuritis (34.6% vs 32%), with no statistical differences (p = 0.716). Median EDSS at sampling was 3.2 (interquartile range [IQR] 2-7.7) in the AQP4+NMOSD group and 4 (IQR [3-6]) in the DS-NMOSD group (p = 0.974). Serum GFAP, tau, and UCH-L1 levels were higher in patients with AQP4+NMOSD compared with those with DS-NMOSD (median 308.3 vs 103.4 pg/mL p = 0.001; median 1.2 vs 0.5 pg/mL, p = 0.001; and median 61.4 vs 35 pg/mL, p = 0.006, respectively). The ROC curve analysis showed that GFAP, tau, and UCH-L1, but not NfL, values were able to discriminate between AQP4+ and DS-NMOSD (area under the curve (AUC) tau: 0.782, p = 0.001, AUC GFAP: 0.762, p = 0.001, AUC UCH-L1: 0.723, p = 0.006). NfL levels were associated with EDSS at nadir only in patients with AQP4+NMOSD. DISCUSSION: Serum GFAP, tau, and UCH-L1 levels discriminate between AQP4+NMOSD and DS-NMOSD. The different biomarker profile of AQP4+NMOSD vs DS-NMOSD suggests heterogeneity of diseases within the latter category and provides useful data to improve our understanding of this disease.

Cerebrospinal fluid neurofilament light chains predicts early disease-activity in Multiple Sclerosis.

BACKGROUND: Among biomarkers of axonal damage, neurofilament light chains (NFL) seem to play a major role, representing a promising and interesting tool in Multiple Sclerosis (MS). Our aim was to explore the predictive role of cerebrospinal fluid (CSF) NFL in patients with a recent diagnosis of MS, naïve to any MS therapy. METHODS: We retrospectively collected data of patients diagnosed with MS, referred to the Neurology Clinic of the University-Hospital G. Rodolico of Catania between January 1st 2005 and December 31st 2015. All patients underwent CSF collection at the time of MS diagnosis and were followed-up for at least three years afterwards. NFL levels were measured in CSF samples with Simoa NFLight advantage kit at the CRESM (University Hospital San Luigi Gonzaga, Orbassano, Torino). NFL levels were expressed as LogNFL. Symbol Digit Modalities test (SDMT) was performed at baseline, at 1-year and at 3-year follow-up. Multivariate logistic regression analysis was performed to investigate LogNFL as a potential risk factor of different clinical outcomes. RESULTS: 244 MS patients (230 relapsing-remitting, RRMS; 94.3 %), with a mean age at diagnosis of 37.0 ± 11.1 years, were recruited. LogNFL did not correlate neither with EDSS score at diagnosis and at subsequent follow-up up to 12 years, nor with SDMT performed at diagnosis, at 1 year and at 3 years. LogNFL were an independent factor for the occurrence of at least one relapse during the first two years after MS diagnosis (OR = 2.75; 95 % CI 1.19-6.31; p = 0.02) and for the occurrence of gadolinium-enhanced (Gd+) lesions during the first 2 years from diagnosis at brain and spine MRI scans (OR = 3.45, 95 % CI 1.81-6.57; p < 0.001). CONCLUSION: The detection of CSF NFL at the time of MS diagnosis can be a useful support to predict the two-year risk of clinical and radiological relapses, thus affecting therapeutic choices in the very early phases of the disease.

Daytime sleepiness and sleep quality in Charcot-Marie-Tooth disease.

BACKGROUND: Sleep abnormalities have been reported in Charcot-Marie-Tooth disease (CMT), but data are scanty. We investigated their presence and correlation in a large CMT patients' series. METHODS: Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI) were administered to CMT patients of the Italian registry and controls. ESS score > 10 indicated abnormal daytime somnolence, PSQI score > 5 bad sleep quality. We analyzed correlation with disease severity and characteristics, Hospital Anxiety and Depression Scale (HADS), Modified Fatigue Impact Scale (MFIS), Body Mass Index, drug use. RESULTS: ESS and PSQI questionnaires were filled by 257 and 253 CMT patients, respectively, and 58 controls. Median PSQI score was higher in CMT patients than controls (6 vs 4, p = 0.006), with no difference for ESS score. Abnormal somnolence and poor sleep quality occurred in 23% and 56% of patients; such patients had more frequently anxiety/depression, abnormal fatigue, and positive sensory symptoms than those with normal ESS/PSQI. Moreover, patients with PSQI score > 5 had more severe disease (median CMT Examination Score, CMTES, 8 vs 6, p = 0.006) and more frequent use of anxiolytic/antidepressant drugs (29% vs 7%, p < 0.001). CONCLUSIONS: Bad sleep quality and daytime sleepiness are frequent in CMT and correlated with anxiety, depression and fatigue, confirming that different components affect sleep. Sleep disorders, such as sleep apnea and restless leg syndrome, not specifically investigated here, are other factors known to impact on sleep quality and somnolence. CMT patients' management must include sleep behavior assessment and evaluation of its correlated factors, including general distress and fatigue.

Quality of care provided by Multiple Sclerosis Centers during Covid-19 pandemic: Results of an Italian multicenter patient-centered survey.

BACKGROUND: Covid-19 pandemic impacted on management of people with Multiple Sclerosis (pwMS). Level of satisfaction of pwMS regarding the care received by the staff of Multiple Sclerosis Centers (MSCs) during the pandemic was not fully investigated. In a large patient-centered multicenter study, the therapeutic adherence and quality of care of MSCs was assessed. METHODS: In April-May 2021, an online survey was widespread by 16 Italian MSCs. Frequencies, percentages and/or means and standard deviations were calculated to describe the sample. ANOVAs were performed to evaluate the effect of sociodemographic and clinical variables on overall pwMS' rating of MSC assistance. RESULTS: 1670 pwMS completed the survey (67.3% women). During the pandemic, 88% did not change their disease modifying therapy schedule, and 89.1% reached their MSCs with no or little difficulties. Even if only 1.3% of participants underwent a tele-health follow-up visit with their MSC staff, the 80.1% believed that tele-health services should be improved regardless of pandemic. 92% of participants were satisfied of how their MSC took charge of their needs; ANOVAs revealed an effect of disease duration on pwMS' level of satisfaction on MSCs management during the pandemic. CONCLUSIONS: The results revealed an efficient MSCs response to Covid-19 pandemic and provided the basis for the implementing of tele-health services that would further improve the taking charge of patients, particularly those with longer disease, higher disability, and/or living far from their MSC.

Clinical spectrum and frequency of Charcot-Marie-Tooth disease in Italy: Data from the National CMT Registry.

BACKGROUND AND PURPOSE: Data are reported from the Italian CMT Registry. METHODS: The Italian CMT Registry is a dual registry where the patient registers and chooses a reference center where the attending clinician collects a minimal dataset of information and administers the Charcot-Marie-Tooth (CMT) Examination/Neuropathy Score. Entered data are encrypted. RESULTS: Overall, 1012 patients had registered (535 females) and 711 had received a genetic diagnosis. Demyelinating CMT (65.3%) was more common than axonal CMT2 (24.6%) and intermediate CMT (9.0%). The PMP22 duplication was the most frequent mutation (45.2%), followed by variants in GJB1 and MPZ (both ~10%) and MFN2 (3.3%) genes. A relatively high mutation rate in some "rare" genes (HSPB1 1.6%, NEFL 1.5%, SH3TC2 1.5%) and the presence of multiple mutation clusters across Italy was observed. CMT4A was the most disabling type, followed by CMT4C and CMT1E. Disease progression rate differed depending on the CMT subtype. Foot deformities and walking difficulties were the main features. Shoe inserts and orthotic aids were used by almost one-half of all patients. Scoliosis was present in 20% of patients, especially in CMT4C. Recessive forms had more frequently walking delay, walking support need and wheelchair use. Hip dysplasia occurred in early-onset CMT. CONCLUSIONS: The Italian CMT Registry has proven to be a powerful data source to collect information about epidemiology and genetic distribution, clinical features and disease progression of CMT in Italy and is a useful tool for recruiting patients in forthcoming clinical trials.

Tailoring Rituximab According to CD27-Positive B-Cell versus CD19-Positive B-Cell Monitoring in Neuromyelitis Optica Spectrum Disorder and MOG-Associated Disease: Results from a Single-Center Study.

INTRODUCTION: B-cell-depleting agents have been widely used for neuromyelitis optica spectrum disorder (NMOSD) and MOG-associated diseases (MOGAD), but no consensus exists on the optimal dose and frequency of treatment administration. The aim of our study was to evaluate the effect of a Rituximab (RTX) personalized treatment approach based on CD27-positive B-cell monitoring on efficacy, safety, and infusion rates. METHODS: This is a retrospective, uncontrolled, single-center study including patients with NMOSD and MOGAD treated with RTX at a tertiary multiple sclerosis center at the San Luigi University Hospital, Orbassano, Italy. All the patients were treated with RTX induction, followed by maintenance infusion at the dosage of 1000 mg according to cell repopulation: initially according to total CD19-positive B-cell monitoring (> 0.1% of lymphocytes), and subsequently according to CD27-positive B-cell repopulation (> 0.05% of lymphocytes for the first 2 years, and subsequently > 0.1%). NMOSD and MOGAD activity was assessed as clinical or MRI activity. All patients were screened of the occurrence of severe adverse events (AEs). RESULTS: A total of 19 patients were included in the analysis. Median follow-up was 7.64 years (range 3.09-16.25). The annualized relapse rate (ARR) 1 year before RTX start was 2.37 [Standard deviation (SD), 1.34] and decreased to 0.08 (SD 0.11) in the subsequent years after RTX initiation. ARR did not differ before and after start of CD27 monitoring. Median inter-dose time was 8.80 (range 5.78-14.23) before CD27 monitoring and 15.93 months (range 8.56-35.37) after CD27 monitoring (p < 0.001). We observed no AEs. CONCLUSION: Our findings suggest that in our cohort CD27-positive B-cell-based RTX reinfusion regimen was able to reduce the number of RTX reinfusions relative to CD19-positive B-cell monitoring, with comparable efficacy and safety profile. In order to achieve an even more individualized and effective treatment, the FCGR3A genetic polymorphisms could be evaluated when assessing RTX efficacy.

Previous disease-modifying treatments influence T lymphocyte kinetics in people with multiple sclerosis switching to ocrelizumab.

BACKGROUND: Recently, concern has been raised about the influence of the previous disease-modifying treatments (DMTs) on the clinical efficacy of ocrelizumab (OCR). We aimed to evaluate whether the previous DMT affects the lymphocyte subset kinetics in people with Multiple Sclerosis (MS) switching to OCR. METHODS: This is a multicenter, retrospective, real-world study on consecutive MS patients who started or switched to OCR. We grouped them by prior DMT in: (i) naïve-to-treatment (NTT), (ii) switching from fingolimod (SF) and (iii) switching from natalizumab (SN). Differences in absolute lymphocyte count and lymphocyte subset count changes, considering the period from baseline to 6 months, over all the three groups were assessed with an inverse-probability-weighted regression adjustment model. RESULTS: Mean T CD4+ cell count reduction from baseline to the six-month follow-up was more pronounced in the SN group compared to the NTT (p = 0,026). Further, patients in the SF group experienced a less pronounced CD4 T cell number decrease than both NTT and SN groups (p = 0,04 and p < 0,001, respectively). Patients in the SF group experienced an increase in CD8 T cell absolute number, whereas those in the NTT and SN groups experienced a significant decrease (p = 0,015 and p < 0,001, respectively). Patients experiencing early inflammatory activity showed a lower CD8+ cell count at baseline than stable patients (p = 0,02). CONCLUSIONS: Previous DMTs influence the lymphocyte kinetics in people with MS switching to OCR. Reassessment of these findings over a larger population may help optimize the switch.

Anxiety and depression in Charcot-Marie-Tooth disease: data from the Italian CMT national registry.

BACKGROUND: There is little information about neuropsychiatric comorbidities in Charcot-Marie-Tooth disease (CMT). We assessed frequency of anxiety, depression, and general distress in CMT. METHODS: We administered online the Hospital Anxiety-Depression Scale (HADS) to CMT patients of the Italian registry and controls. HADS-A and HADS-D scores ≥ 11 defined the presence of anxiety/depression and HADS total score (HADS-T) ≥ 22 of general distress. We analysed correlation with disease severity and clinical characteristics, use of anxiolytics/antidepressants and analgesic/anti-inflammatory drugs. RESULTS: We collected data from 252 CMT patients (137 females) and 56 controls. CMT patient scores for anxiety (mean ± standard deviation, 6.7 ± 4.8), depression (4.5 ± 4.0), and general distress (11.5 ± 8.1) did not differ from controls and the Italian population. However, compared to controls, the percentages of subjects with depression (10% vs 2%) and general distress (14% vs 4%) were significantly higher in CMT patients. We found no association between HADS scores and disease duration or CMT type. Patients with general distress showed more severe disease and higher rate of positive sensory symptoms. Depressed patients also had more severe disease. Nineteen percent of CMT patients took antidepressants/anxiolytics (12% daily) and 70% analgesic/anti-inflammatory drugs. Patients with anxiety, depression, and distress reported higher consumption of anxiolytics/antidepressants. About 50% of patients with depression and/or general distress did not receive any specific pharmacological treatment. CONCLUSIONS: An appreciable proportion of CMT patients shows general distress and depression. Both correlated with disease severity and consumption of antidepressants/anxiolytics, suggesting that the disease itself is contributing to general distress and depression.

Frequency, entity and determinants of fatigue in Charcot-Marie-Tooth disease.

BACKGROUND AND PURPOSE: Fatigue, a disabling symptom in many neuromuscular disorders, has been reported also in Charcot-Marie-Tooth disease (CMT). The presence of fatigue and its correlations in CMT was investigated. METHODS: The Modified Fatigue Impact Scale (MFIS) was administered to CMT patients from the Italian Registry and a control group. An MFIS score >38 indicated abnormal fatigue. The correlation with disease severity and clinical characteristics, the Hospital Anxiety and Depression Scale and Epworth Sleepiness Scale scores, and drug use was analysed. RESULTS: Data were collected from 251 CMT patients (136 women) and 57 controls. MFIS total (mean ± standard deviation 32 ± 18.3, median 33), physical (18.9 ± 9.7, 20) and psychosocial (2.9 ± 2.4, 3) scores in CMT patients were significantly higher than controls. Abnormal fatigue occurred in 36% of the patients who, compared to patients with normal scores, had more severe disease (median CMT Examination Score 9 vs. 7), more frequent use of foot orthotics (22% vs. 11%), need of support for walking (21% vs. 8%), hand disability (70% vs. 52%) and positive sensory symptoms (56% vs. 36%). Patients with abnormal fatigue had significantly increased frequency of anxiety/depression/general distress (Hospital Anxiety and Depression Scale), somnolence (Epworth Sleepiness Scale), obesity (body mass index ≥ 30) and use of anxiolytic/antidepressant or anti-inflammatory/analgesic drugs. CONCLUSIONS: Fatigue is a relevant symptom in CMT as 36% of our series had scores indicating abnormal fatigue. It correlated with disease severity but also with anxiety, depression, sleepiness and obesity, indicating different components in the generation of fatigue. CMT patients' management must include treatment of fatigue and of its different generators, including general distress, sleepiness and obesity.