Disease-modifying therapies in managing disability worsening in paediatric-onset multiple sclerosis: a longitudinal analysis of global and national registries.

BACKGROUND: High-efficacy disease-modifying therapies have been proven to slow disability accrual in adults with relapsing-remitting multiple sclerosis. However, their impact on disability worsening in paediatric-onset multiple sclerosis, particularly during the early phases, is not well understood. We evaluated how high-efficacy therapies influence transitions across five disability states, ranging from minimal disability to gait impairment and secondary progressive multiple sclerosis, in people with paediatric-onset multiple sclerosis. METHODS: Longitudinal data were obtained from the international MSBase registry, containing data from people with multiple sclerosis from 151 centres across 41 countries, and the Italian Multiple Sclerosis and Related Disorders Register, containing data from people with multiple sclerosis from 178 Italian multiple sclerosis centres. People younger than 18 years at the onset of multiple sclerosis symptoms were included, provided they had a confirmed diagnosis of relapsing-remitting multiple sclerosis and at least four Expanded Disability Status Scale (EDSS) scores recorded within 12-month intervals. The primary outcome was the time to change in disability state: minimal disability (EDSS scores 0, 1·0, and 1·5), mild disability (EDSS scores 2·0 and 2·5), moderate disability (EDSS scores 3·0 and 3·5), gait impairment (EDSS scores ≥4·0), and clinician diagnosed secondary progressive multiple sclerosis. A multi-state model was constructed to simulate the natural course of multiple sclerosis, modelling the probabilities of both disability worsening and improvement simultaneously. The impact of high-efficacy disease-modifying therapies (alemtuzumab, cladribine, daclizumab, fingolimod, mitoxantrone, natalizumab, ocrelizumab, rituximab, or autologous haematopoietic stem cell transplantation) and low-efficacy disease-modifying therapies (dimethyl fumarate, glatiramer acetate, interferon beta, or teriflunomide), compared with no treatment, on the course of disability was assessed. Apart from recruitment, individuals with lived experience of multiple sclerosis were not involved in the design and conduct of this study. FINDINGS: A total of 5224 people (3686 [70·6%] female and 1538 [29·4%] male) with mean age at onset of multiple sclerosis 15·24 years (SD 2·52) were included. High-efficacy therapies reduced the hazard of disability worsening across the disability states. The largest reduction (hazard ratio 0·41 [95% CI 0·31-0·53]) was observed in participants who were treated with high-efficacy therapies while in the minimal disability state, compared with those remained untreated. The benefit of high-efficacy therapies declined with increasing disability. Young people with minimal disability who received low-efficacy therapy also experienced a reduced hazard (hazard ratio 0·65 [95% CI 0·54-0·77]) of transitioning to mild disability, in contrast to those who remained untreated. INTERPRETATION: Treatment of paediatric-onset relapsing-remitting multiple sclerosis with high-efficacy therapy substantially reduces the risk of reaching key disability milestones. This reduction in risk is most pronounced among young people with minimal or mild disability when treatment began. Children with relapsing-remitting multiple sclerosis should be treated early with high-efficacy therapy, before developing significant neurological impairments, to better preserve their neurological capacity. FUNDING: National Health and Medical Research Council, Australia; MSBase Foundation Fellowship; MS Australia Postdoctoral Fellowship.

Treatment modifiers across different regimens of natalizumab treatment in MS: An Italian real-world experience.

Despite its widespread use in clinical practice, the effectiveness of natalizumab extended interval dosing (EID) adopted from treatment start across different treatment intervals and individual modifiers (body mass index - BMI) is still under-investigated. Here, seven-hundred and forty-five multiple sclerosis (MS) patients, exposed to natalizumab for 3.30 â€‹± â€‹1.34 years, were retrospectively enrolled in an observational multicenter study. After stratifying patients in EID or standard interval dosing (SID), we assessed differences in time to relapse, MRI activity and Expanded Disability Status Scale (EDSS) progression. The primary analysis was conducted on patients exposed to EID interval from 5 weeks and 1 day to 7 weeks, while a secondary analysis included also EID periods up to 8 weeks. An additional analysis explored the impact of BMI. No differences in time to first relapse, time to radiological activity, time to EDSS progression or time to EDA (evidence of disease activity) were detected between SID and EID group (EID interval from 5 weeks to 1 day to 7 weeks). When including EID periods from 7 weeks and 1 day to 8 weeks, the EID group showed a trend towards higher risk of experience clinical relapses than the SID group. A higher EDA risk was also identified in EID patients with BMI above median. In conclusion, a higher risk of relapses seems to occur for EID above 7 weeks. Independently from the EID scheme adopted, higher BMI increases the risk of EDA in these patients.

The role of ethnicity and native-country income in multiple sclerosis: the Italian multicentre study (MS-MigIT).

OBJECTIVE: Multiple sclerosis (MS) is a complex disorder in which environmental and genetic factors interact modifying disease risk and course. This multicentre, case-control study involving 18 Italian MS Centres investigated MS course by ethnicity and native-country economic status in foreign-born patients living in Italy. METHODS: We identified 457 MS patients who migrated to Italy and 893 age- and sex-matched native-born Italian patients. In our population, 1225 (93.2%) subjects were White Europeans and White Northern Americans (WENA) and 89 (6.8%) patients were from other ethnical groups (OEG); 1109 (82.1%) patients were born in a high-income (HI) Country and 241 (17.9%) in a low-middle-income (LMI) Country. Medical records and patients interviews were used to collect demographic and disease data. RESULTS: We included 1350 individuals (973 women and 377 men); mean (SD) age was 45.0 (11.7) years. At onset, 25.45% OEG patients vs 12.47% WENA (p = 0.039) had > 3 STIR spine lesions. At recruitment, the same group featured mean (SD) EDSS score of 2.85 (2.23) vs 2.64 (2.28) (p = 0.044) reached in 8.9 (9.0) vs 12.0 (9.0) years (p = 0.018) and underwent 1.10 (4.44) vs. 0.99 (0.40) annual MRI examinations (p = 0.035). At disease onset, patients from LMI countries had higher EDSS score than HI patients (2.40 (1.43) vs 1.99 (1.17); p = 0.032). DISCUSSION: Our results suggested that both ethnicity and socio-economic status of native country shape MS presentation and course and should be considered for an appropriate management of patients. To the best of our knowledge, this is the first study reporting on the impact of ethnicity in MS at an individual level and beyond an ecological population-perspective.

Late-onset multiple sclerosis: disability trajectories in relapsing-remitting patients of the Italian MS Registry.

BACKGROUND: Generally infrequent, multiple sclerosis (MS) with late onset (LOMS) is characterized by an onset over the age of 50 and a mainly progressive course, while relapsing-remitting (RR) forms are less frequently observed and explored. This study aimed to characterize a large cohort of MS patients with RRMS at onset to assess the baseline factors related to the worst disability trajectories and explore the role of LOMS. METHODS: The data were extracted from the Italian MS Register (IMSR). Disability trajectories, defined using at least two and up to twenty expanded disability status scale (EDSS) assessments annually performed, were implemented using group-based trajectory models (GBTMs) to identify different groups with the same trajectories over time. MS profiles were explored using multinomial logistic regression. RESULTS: A total of 16,159 RR patients [1012 (6.26%) presented with LOMS] were analyzed. The GBTM identified four disability trajectories. The group with the most severe EDSS trend included 12.3% of the patients with a mean EDSS score > 4, which increased over time and exceeded 6 score. The group with medium severity EDSS trend comprised 21.9% of the patients and showed a change in EDSS > 3 scores over time. The largest group with 50.8% of patients reported a constant EDSS of 2 score. Finally, the benign group comprised 14.9% of the patients with a low and constant EDSS of 1 score over time. The probability of being in the worst groups increased if the patient was male; had LOMS or experienced brainstem, spinal, or supratentorial symptoms. CONCLUSIONS: Four MS severity profiles among RRMS patients in the IMSR have been reported, with LOMS being associated with a rapid worsening of EDSS scores. These findings have important implications for recognizing and managing how older age, aging, and age-related factors interact with MS and its evolution.

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.

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.

Tocilizumab treatment in MOGAD: a case report and literature review.

Myelin oligodendrocyte glycoprotein-immunoglobulin G associated disease (MOGAD) is an autoimmune demyelinating disorder of the central nervous system (CNS) which usually occurs with recurrent optic neuritis, transverse myelitis, acute disseminating encephalomyelitis, or brainstem encephalitis. To date, the anti-CD 20 drug rituximab (RTX) is employed in MOGAD although some authors reported the efficacy of Tocilizumab (TCZ) in refractory patients. We present the case of a woman affected by refractory MOGAD who was treated with TCZ after therapy with RTX had failed to prevent relapses. We also conducted a current literature review on TCZ use in MOGAD. A 57-year-old Caucasian woman affected by MOGAD with severe motor impairment and cognitive dysfunction was treated from 2020 to February 2022 with RTX. However, she experienced progressive clinical and cognitive worsening associated with white matter lesions mimicking leukodystrophy. In February 2022, the patient started therapy with TCZ administered with improvement of cognitive performance, walking ability, and brainstem functions. During TCZ, our patient reached the condition of NEDA-3 (no relapse, no increase in disability, no MRI activity on neuroimaging follow-up performed in September 2023). Moreover, the patient experienced paucisymptomatic SARS-CoV-2 infection that did not modify TCZ schedule. To date, there are few evidence on the efficacy and safety of TCZ in MOGAD. However, all the reviewed cases showed that TCZ represents an effective therapy in drug-resistant MOGAD. Our case highlights the efficacy of TCZ in drug resistant MOGAD and strengthens previous reports of TCZ safety and efficacy in MOGAD.

Orofacial Migraine and Other Idiopathic Non-Dental Facial Pain Syndromes: A Clinical Survey of a Social Orofacial Patient Group.

Background: Orofacial pain syndromes (OFPs) are a heterogeneous group of syndromes mainly characterized by painful attacks localized in facial and oral structures. According to the International Classification of Orofacial Pain (ICOP), the last three groups (non-dental facial pain, NDFP) are cranial neuralgias, facial pain syndromes resembling primary headache syndromes, and idiopathic orofacial pain. These are often clinical challenges because the symptoms may be similar or common among different disorders. The diagnostic efforts often induce a complex diagnostic algorithm and lead to several imaging studies or specialized tests, which are not always necessary. The aim of this study was to describe the encountered difficulties by these patients during the diagnostic-therapeutic course. Methods: This study was based on the responses to a survey questionnaire, administered to an Italian Facebook Orofacial Patient Group, searching for pain characteristics and diagnostic-therapeutic care courses. The questionnaire was filled out by patients affected by orofacial pain, who were 18 years and older, using a free online tool available on tablets, smartphones, and computers. Results: The sample was composed of 320 subjects (244F/76M), subdivided by age range (18-35 ys: 17.2%; 36-55 ys: 55.0%; >55 ys 27.8%). Most of the patients were affected by OFP for more than 3 years The sample presented one OFP diagnosis in 60% of cases, more than one in 36.2% of cases, and 3.8% not classified. Trigeminal neuralgia is more represented, followed by cluster headaches and migraines. About 70% had no pain remission, showing persisting background pain (VAS median = 7); autonomic cranial signs during a pain attack ranged between 45 and 65%. About 70% of the subjects consulted at least two different specialists. Almost all received drug treatment, about 25% received four to nine drug treatments, 40% remained unsatisfied, and almost 50% received no pharmacological treatment, together with drug therapy. Conclusion: To the authors' knowledge, this is the first study on an OFP population not selected by a third-level specialized center. The authors believe this represents a realistic perspective of what orofacial pain subjects suffer during their diagnostic-therapeutic course and the medical approach often results in unsatisfactory outcomes.

Role of the immune system in amyotrophic lateral sclerosis. Analysis of the natural killer cells and other circulating lymphocytes in a cohort of ALS patients.

AIMS: Neuroinflammation might be involved in the degeneration and progression of Amyotrophic Lateral Sclerosis (ALS). Here, we studied the role of the circulating lymphocytes in ALS, in particular the NK cells. We focused on the relationship between blood lymphocytes, ALS clinical subtype and disease severity. SUBJECTS AND METHODS: Blood samples were collected from 92 patients with sporadic ALS, 21 patients with Primary Lateral Sclerosis (PLS) and 37 patients affected by primary progressive multiple sclerosis (PPMS) with inactive plaques. Blood was taken from ALS and controls at the time of diagnosis/referral. Circulating lymphocytes were analyzed by flow cytometry with specific antibodies. Values were expressed as absolute number (n°/µl) of viable lymphocytes subpopulations in ALS were compared with controls. Multivariable analysis was made using site of onset, gender changes in ALSFRS-R and disease progression rate (calculated as ΔFS score). RESULTS: Age at onset was 65y (58-71) in ALS (spinal 67.4%; bulbar, 32.6%), 57y (48-78) in PLS and 56y (44-68) PPMS. Absolute blood levels of the lymphocytes in the different cohorts were within normal range. Furthermore, while levels of lymphocytes T and B were not different between disease groups, NK cells were increased in the ALS cohort (ALS = 236 [158-360] vs. Controls = 174[113-240], p < 0.001). In ALS, blood levels of NK cells were not related with the main clinical-demographic variables, including the rate of disease progression. Multivariable analysis suggested that male gender and bulbar onset were independently associated with a risk of high blood NK cells levels. CONCLUSIONS: We show that blood NK cells are selectively increased in ALS, though their level appear unaffected in patients with an estimated rapidly progressing disease. Being of a male gender and with a bulbar onset seems to confer higher susceptibility to have increased NK lymphocytes levels at diagnosis/referral. Our experiments provides a further clear-cut evidence of the role of the NK lymphocytes as a significant player in ALS pathogenesis.

Evaluation of serum and cerebrospinal fluid biomarkers after vaccination against SARS-CoV-2.

OBJECTIVE: Vaccines are a major achievement of science, and new vaccines against SARS-CoV-2 are protecting the entire population from a life-threatening infection. Although several neurological complications or worsening of pre-existing neurological conditions after vaccination have been observed, whether a biological plausibility exist between new vaccines against-SARS-CoV-2 and neurological consequences is unclear. The aim of this study is to evaluate whether vaccines against SARS-CoV-2 induce systemic or cerebrospinal fluid alterations in patients with neurological disorders. METHODS: Patients who underwent lumbar puncture (LP) between February 2021 and October 2022 were enrolled. Serum C-reactive protein (CRP), neutrophil to lymphocyte ratio (NLR), cerebrospinal fluid total protein content (CSF-TPc), glucose CSF/serum ratio, number of CSF cells per cubic millimeter, and CSF neurofilament light chain (CSF-NfL) were compared between unvaccinated and vaccinated patients. RESULTS: A total of 110 patients were included and fitted into three groups according firstly to vaccination status (vaccinated and unvaccinated) and then to time from last dose of vaccine to LP (within or after 3 months). TPc, CSF/SGlu ratio, number of cells per cubic millimeter, CSF-NfL, CRP, and NLR were not different between groups (all p > 0.05), and also, they did not differ neither according to age nor diagnosis. No relevant differences between groups were also noticed when the at-risk time window was set to 6 weeks. INTERPRETATION: No signs of neuroinflammation, axonal loss and systemic inflammation were found in patients with neurological disorders after anti-SARS-CoV-2 vaccination compared with unvaccinated ones.

Impact of treatment with dimethyl fumarate on sleep quality in patients with relapsing-remitting multiple sclerosis: A multicentre Italian wearable tracker study.

Background: Sleep disorders are common in patients with multiple sclerosis and have a bidirectional interplay with fatigue and depression. Objective: To evaluate the effect of treatment with oral dimethyl fumarate on the quality of sleep in relapsing-remitting multiple sclerosis. Methods: This was a multicentre observational study with 223 relapsing-remitting multiple sclerosis subjects starting treatment with dimethyl fumarate (n=177) or beta interferon (n=46). All patients underwent subjective (Pittsburgh Sleep Quality Index) and objective (wearable tracker) measurements of quality of sleep. Fatigue, depression, and quality of life were also investigated and physical activity was monitored. Results: Patients treated with dimethyl fumarate had significant improvement in the quality of sleep as measured with the Pittsburgh Sleep Quality Index (p<0.001). At all-time points, no significant changes in Pittsburgh Sleep Quality Index score were observed in the interferon group. Total and deep sleep measured by wearable tracker decreased at week 12 with both treatments, then remained stable for the total study duration. Depression significantly improved in patients treated with dimethyl fumarate. No significant changes were observed in mobility, fatigue and quality of life. Conclusion: In patients with relapsing-remitting multiple sclerosis, the treatment with dimethyl fumarate was associated with improvements in patient-reported quality of sleep. Further randomised clinical trials are needed to confirm the benefits of long-term treatment with dimethyl fumarate.

Microchimerism in multiple sclerosis: The association between sex of offspring and MRI features in women with multiple sclerosis.

Aims: During pregnancy, fetal cells can migrate to the mother via blood circulation. A percentage of these cells survive in maternal tissues for decades generating a population of fetal microchimeric cells (fMCs), whose biological role is unclear. The aim of this study was to investigate the association between the sex of offspring, an indirect marker of fMCs, and magnetic resonance imaging (MRI) features in women with multiple sclerosis (MS). Methods: We recruited 26 nulliparous MS patients (NPp), 20 patients with at least one male son (XYp), and 8 patients with only daughters (XXp). Each patient underwent brain MR scan to acquire 3D-T2w FLAIR FatSat and 3D-T1w FSPGR/TFE. Lesion Segmentation Tool (LST) and FreeSurfer were used to obtain quantitative data from MRI. Additional data were collected using medical records. Multiple regression models were applied to evaluate the association between sex of offspring and MS data. Results: Comparing NPp and XXp, we found that NPp had larger 4th ventricle volume (2.02 ± 0.59 vs. 1.70 ± 0.41; p = 0.022), smaller left entorhinal volume (0.55 ± 0.17 vs. 0.68 ± 0.25; p = 0.028), and lower thickness in the following cortical areas: left paracentral (2.34 ± 0.16 vs. 2.39 ± 0.17; p = 0.043), left precuneus (2.27 ± 0.11 vs. 2.34 ± 0.16; p = 0.046), right lateral occipital (2.14 ± 0.11 vs. 2.25 ± 0.08; p = 0.006). NPp also had lower thickness in left paracentral cortex (2.34 ± 0.16 vs. 2.46 ± 0.17; p = 0.004), left precalcarine cortex (1.64 ± 0.14 vs. 1.72 ± 0.12; p = 0.041), and right paracentral cortex (2.34 ± 0.17 vs. 2.42 ± 0.14; p = 0.015) when compared to XYp. Comparing XYp and XXp, we found that XYp had higher thickness in left cuneus (1.80 ± 0.14 vs. 1.93 ± 0.10; p = 0.042) and left pericalcarine areas (1.59 ± 0.19 vs. 1.72 ± 0.12; p = 0.032) and lower thickness in right lateral occipital cortex (2.25 ± 0.08 vs. 2.18 ± 0.13; p = 0.027). Discussion: Our findings suggested an association between the sex of offspring and brain atrophy. Considering the sex of offspring as an indirect marker of fMCs, we speculated that fMCs could accumulate in different brain areas modulating MS neuropathological processes.

Unmet needs and gaps in the identification of secondary progression in multiple sclerosis: a Southern Italy healthcare professionals' perspective.

OBJECTIVE: Multiple sclerosis (MS) is a chronic disease with different clinical courses and a tendency to worsening. The relapsing-remitting MS presents acute onset and relapses of neurological symptoms, followed by their remission. This form can convert to secondary progressive MS (SPMS) with irreversible neurological worsening and disability. The identification of signs, symptoms, markers of progression, and strategies to manage MS patients is mandatory to allow early identification of those at higher risk of conversion to SPMS, for prompt intervention to cope with the progression of the disease. METHODS: A panel of Italian experts from Southern Italy have reviewed the current knowledge on MS and its management and identified the crucial tools for SPMS recognition. RESULTS: More effective communication between patients and clinicians should be established, with the support of digital tools. Moreover, the improvement in the clinical use of biomarkers for progression (cellular structures and tissue organization, such as neurofilaments and chitinase 3-like 1, axonal and neurons density) and of instrumental analyses for recognition of whole-brain atrophy, chronic active lesions, spinal cord lesions and atrophy, and the improvement the combination of the Expanded Disability Status Scale and the evaluation of cognitive dysfunction are discussed. CONCLUSION: Given the availability of a pharmacological option, adequate education both for patients, regarding the evolution of the disease and the specific treatment, and for professionals, to allow more effective and sensitive communication and the best use of diagnostic and management tools, could represent a strategy to improve patient management and their quality of life.

Hematopoietic Stem Cell Transplantation in People With Active Secondary Progressive Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Uncontrolled evidence suggests that autologous hematopoietic stem cell transplantation (AHSCT) can be effective in people with active secondary progressive multiple sclerosis (SPMS). In this study, we compared the effect of AHSCT with that of other anti-inflammatory disease-modifying therapies (DMTs) on long-term disability worsening in active SPMS. METHODS: We collected data from the Italian Bone Marrow Transplantation Study Group and the Italian Multiple Sclerosis Register. Patients were considered eligible if treatment had been started after the diagnosis of SPMS. Disability worsening was assessed by the cumulative proportion of patients with a 6-month confirmed disability progression (CDP) according to the Expanded Disability Status Scale (EDSS) score. Key secondary endpoints were the EDSS time trend after treatment start and the prevalence of disability improvement over time. Time to first CDP was assessed by means of proportional hazard Cox regression models. A linear mixed model with a time × treatment group interaction was used to assess the longitudinal EDSS time trends. Prevalence of improvement was estimated using a modified Kaplan-Meier estimator and compared between groups by bootstrapping the area under the curve. RESULTS: Seventy-nine AHSCT-treated patients and 1975 patients treated with other DMTs (beta interferons, azathioprine, glatiramer-acetate, mitoxantrone, fingolimod, natalizumab, methotrexate, teriflunomide, cyclophosphamide, dimethyl fumarate, and alemtuzumab) were matched to reduce treatment selection bias using propensity score and overlap weighting approaches. Time to first CDP was significantly longer in transplanted patients (hazard ratio [HR] = 0.50; 95% CI = 0.31-0.81; p = 0.005), with 61.7% of transplanted patients free from CPD at 5 years. Accordingly, EDSS time trend over 10 years was higher in patients treated with other DMTs than in AHSCT-treated patients (+0.157 EDSS points per year compared with -0.013 EDSS points per year; interaction p < 0.001). Patients who underwent AHSCT were more likely to experience a sustained disability improvement: 34.7% of patients maintained an improvement (a lower EDSS than baseline) 3 years after transplant vs 4.6% of patients treated by other DMTs (p < 0.001). DISCUSSION: The use of AHSCT in people with active SPMS is associated with a slowing of disability progression and a higher likelihood of disability improvement compared with standard immunotherapy. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that autologous hematopoietic stem cell transplants prolonged the time to CDP compared with other DMTs.

Off-Adherence Keeping (OAK) observational study: intentional off-adherence immunomodulatory multiple sclerosis treatment.

Aims: To evaluate how improved treatment adherence with a lower-frequency regimen/treatment of intramuscular (IM) IFNß-1a impacts therapeutic effectiveness in relapsing-remitting multiple sclerosis (MS) patients switching from a higher-frequency injectable regimen/treatment. Patients & methods: Italian patients with relapsing-remitting MS and prior poor adherence to high-frequency injectable treatments (n = 181) were followed for 24 months after starting IM IFNß-1a. Results: During the study, 97.4% of patients were treatment adherent; 22.1% of patients reported a relapse. The estimated probability of remaining relapse-free after 2 years was 78%. A high dropout rate (52.5%) led to small sample size and reduced statistical power. Conclusion: Intramuscular IFNß-1a treatment was associated with high adherence and a low relapse rate. Unfortunately, low patient retention limited the generalizability of these findings.

Prior research suggests that taking the drug IFNß-1a through less frequent muscle injections enables more patients to adhere to their prescription than taking other medications. This study included 181 Italian patients with relapsing-remitting multiple sclerosis (MS) who historically did not take medication as often as prescribed. Relapses of MS were counted among patients treated with muscle injections of IFNß-1a for 2 years; 97.4% of patients followed their prescription and 22.1% experienced a relapse. From these data, 78% of patients were estimated not to experience a relapse during 2 years of IFNß-1a muscle injections. However, an unusually high number of patients (52.5%) left the study within 2 years, which makes it difficult to draw firm conclusions.

Towards a validated definition of the clinical transition to secondary progressive multiple sclerosis: A study from the Italian MS Register.

BACKGROUND: Definitions for reliable identification of transition from relapsing-remitting multiple sclerosis (MS) to secondary progressive (SP)MS in clinical cohorts are not available. OBJECTIVES: To compare diagnostic performances of two different data-driven SPMS definitions. METHODS: Data-driven SPMS definitions based on a version of Lorscheider's algorithm (DDA) and on the EXPAND trial inclusion criteria were compared, using the neurologist's definition (ND) as gold standard, in terms of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), Akaike information criterion (AIC) and area under the curve (AUC). RESULTS: A cohort of 10,240 MS patients with ⩾5 years of follow-up was extracted from the Italian MS Registry; 880 (8.5%) patients were classified as SPMS according to the neurologist definition, 1806 (17.6%) applying the DDA and 1134 (11.0%) with the EXPAND definition. The DDA showed greater discrimination power (AUC: 0.8 vs 0.6) and a higher sensitivity (77.1% vs 38.0%) than the EXPAND definition, with similar specificity (88.0% vs 91.5%). PPV and NPV were higher using the DDA than considering EXPAND definition (37.5% vs 29.5%; 97.6% vs 94.0%). CONCLUSION: Data-driven definitions demonstrated greater ability to capture SP transition than neurologist's definition and the global accuracy of DDA seems to be higher than the EXPAND definition.

A Brief Overview on BDNF-Trk Pathway in the Nervous System: A Potential Biomarker or Possible Target in Treatment of Multiple Sclerosis?

The growing incidence of neurodegenerative disorders in our populations is leading the research to identify potential biomarkers and targets for facilitating their early management and treatments. Biomarkers represent the crucial indicators of both physiological and pathological processes. Specific changes in molecular and cellular mechanisms of physiological processes result in biochemical alterations at systemic level, which can give us comprehensive information regarding the nature of any disease. In addition, any disease biomarker should be specific and reliable, able to consent of distinguishing the physiological condition of a tissue, organ, or system from disease, and be diverse among the various diseases, or subgroups or phenotypes of them. Accordingly, biomarkers can predict chances for diseases, facilitate their early diagnosis, and set guidelines for the development of new therapies for treating diseases and disease-making process. Here, we focus our attention on brain neurotrophic factor (BDNF)-tropomyosin receptor kinase (Trk) pathway, describing its multiple roles in the maintenance of central nervous system (CNS) health, as well as its implication in the pathogenesis of multiple sclerosis (MS). In addition, we also evidence the features of such pathway, which make of it a potential MS biomarker and therapeutic target.

Role of Multiple Vitamin D-Related Polymorphisms in Multiple Sclerosis Severity: Preliminary Findings.

BACKGROUND: Multiple Sclerosis (MS) is a multifactorial disease whose pathogenesis is the result of interaction among genetic, epigenetic, and environmental factors. Among these, a role for vitamin D hypovitaminosis has emerged in recent decades. Vitamin D levels are influenced by both environmental and genetic factors. Single nucleotide polymorphisms (SNPs) in genes codifying for molecules involved in vitamin D metabolism have been associated with an increased risk of developing MS. However, few studies assessed the association of such SNPs with the severity of the disease. The aim of this observational study was to evaluate the potential association among vitamin D status, MS severity, and vitamin D-related SNPs, alone or in combination. METHODS: In a cohort of 100 MS patients, we genotyped 18 SNPs in the following genes: NAD synthetase 1, CYP2R1, vitamin D binding protein, vitamin D receptor, Retinoid X Receptor-α, KLOTHO, CYP24A1, and CYP27A1. Serum 25(OH)D3 levels were measured by high-performance liquid chromatography. Genotyping was performed by real-time polymerase chain reaction or PCR-RFLP. RESULTS: We did not find any association between SNPs, alone or in combination, and MS severity. CONCLUSION: In this study, we make an initial evaluation of the possible influence of several SNPs in vitamin D-related genes on MS severity.

Progression is independent of relapse activity in early multiple sclerosis: a real-life cohort study.

Disability accrual in multiple sclerosis may occur as relapse-associated worsening or progression independent of relapse activity. The role of progression independent of relapse activity in early multiple sclerosis is yet to be established. The objective of this multicentre, observational, retrospective cohort study was to investigate the contribution of relapse-associated worsening and progression independent of relapse activity to confirmed disability accumulation in patients with clinically isolated syndrome and early relapsing-remitting multiple sclerosis, assessed within one year from onset and with follow-up ≥5 years (n = 5169). Data were extracted from the Italian Multiple Sclerosis Register. Confirmed disability accumulation was defined by an increase in Expanded Disability Status Scale score confirmed at 6 months, and classified per temporal association with relapses. Factors associated with progression independent of relapse activity and relapse-associated worsening were assessed using multivariable Cox regression models. Over a follow-up period of 11.5 ± 5.5 years, progression independent of relapse activity occurred in 1427 (27.6%) and relapse-associated worsening in 922 (17.8%) patients. Progression independent of relapse activity was associated with older age at baseline [hazard ratio (HR) = 1.19; 95% confidence interval (CI) 1.13-1.25, P < 0.001], having a relapsing-remitting course at baseline (HR = 1.44; 95% CI 1.28-1.61, P < 0.001), longer disease duration at baseline (HR = 1.56; 95% CI 1.28-1.90, P < 0.001), lower Expanded Disability Status Scale at baseline (HR = 0.92; 95% CI 0.88-0.96, P < 0.001) and lower number of relapses before the event (HR = 0.76; 95% CI 0.73-0.80, P < 0.001). Relapse-associated worsening was associated with younger age at baseline (HR = 0.87; 95% CI 0.81-0.93, P < 0.001), having a relapsing-remitting course at baseline (HR = 1.55; 95% CI 1.35-1.79, P < 0.001), lower Expanded Disability Status Scale at baseline (HR = 0.94; 95% CI 0.89-0.99, P = 0.017) and a higher number of relapses before the event (HR = 1.04; 95% CI 1.01-1.07, P < 0.001). Longer exposure to disease-modifying drugs was associated with a lower risk of both progression independent of relapse activity and relapse-associated worsening (P < 0.001). This study provides evidence that in an early relapsing-onset multiple sclerosis cohort, progression independent of relapse activity was an important contributor to confirmed disability accumulation. Our findings indicate that insidious progression appears even in the earliest phases of the disease, suggesting that inflammation and neurodegeneration can represent a single disease continuum, in which age is one of the main determinants of disease phenomenology.

Comparing Natural History of Early and Late Onset Pediatric Multiple Sclerosis.

OBJECTIVE: This study was undertaken to describe and compare disease course and prognosis of early (ie, disease onset before age 11 years) and late (ie, disease onset after age 11 years) onset pediatric multiple sclerosis. METHODS: Prospectively collected clinical information from Italian Multiple Sclerosis Register of 1993 pediatric multiple sclerosis patients, of whom 172 had early onset, was analyzed. Cox models adjusted for sex, baseline Expanded Disability Status Scale score, and disease-modifying treatments and stratified for diagnostic criteria adopted (Poser vs McDonald) were used to assess the risk of reaching irreversible Expanded Disability Status Scale scores of 3, 4, and 6, and conversion to secondary progressive phenotype in early versus late onset pediatric patients. Prognostic factors were also evaluated. RESULTS: A greater proportion of males, isolated brainstem involvement, and longer time interval between first and second clinical episode were observed in early versus late onset pediatric patients. Compared to late onset, early onset pediatric patients took longer from disease onset to convert to secondary progressive phenotype and to reach all disability milestones. Recovery from first demyelinating event, time to first relapse, annualized relapse rate during the first 3 years of disease, and disease-modifying treatment exposure were independent predictors for long-term disability in early onset pediatric patients. In late onset pediatric patients, isolated optic neuritis, multifocal symptoms, and progressive course at disease onset were additional predictors for long-term disability. INTERPRETATION: These findings point toward the existence of a different natural history in early versus late onset pediatric multiple sclerosis patients. ANN NEUROL 2022;91:483-495.