Abstract

Background: Characterizing Cladribine tablets prescription pattern in daily clinical practice is crucial for optimizing multiple sclerosis (MS) treatment.

Objectives: To describe efficacy, safety profile and new disease-modifying therapy (DMT) prescriptions following Cladribine treatment.

Design: Independent retrospective cohort study in patients followed at six Italian MS centres.

Methods: Patients diagnosed with relapsing MS (RMS) according to 2017 McDonald criteria, who initiated Cladribine between January 2019 and May 2023, were included. A generalized linear regression model was built for the outcome DMT after Cladribine course. Heatmaps were generated based on weighted pivot tables to visualize the proportion of patients requiring DMT post-Cladribine.

Results: A total cohort of 352 patients was enrolled, 134 naïve to any DMT, 218 switchers from other DMTs. The last DMT was an injectable first-line DMT for 48 (22%) patients, oral first-line DMT for 141 (64.7%) patients, SP1 inhibitor-Fingolimod for 23 (10.6%) patients, and Natalizumab for 6 (2.7%) patients. Overall, Cladribine was efficacious and well tolerated, 12% of patients required a new DMT prescription after a median time of 24 months. The regression model revealed that patients aged >40 years at Cladribine prescription had a 16% decrease in likelihood of receiving a new DMT. Heatmaps showed patients previously on Fingolimod had a lower rate (72.2%) of being free from therapy after Cladribine.

Conclusion: In our multicentric real-world Italian study, Cladribine therapy is generally effective during the investigated follow-up period. Understanding key characteristics of patients responding best to Cladribine can help tailor therapeutic strategies for optimal outcomes.

Keywords: cladribine; long-term management; multiple sclerosis; prescription pattern.

Abstract

Background and purpose: Cladribine tablets, a purine analogue antimetabolite, offer a unique treatment regimen, involving short courses at the start of the first and second year, with no further treatment needed in years 3 and 4. However, comprehensive evidence regarding patient outcomes beyond the initial 24 months of cladribine treatment is limited.

Methods: This retrospective, multicenter study enrolled 204 patients with multiple sclerosis who had completed the 2-year course of cladribine treatment. The primary outcomes were therapeutic choices and clinical disease activity assessed by annualized relapse rate after the 2-year treatment course.

Results: A total of 204 patients were enrolled; most patients (75.4%) did not initiate new treatments in the 12 months postcladribine. The study found a significant reduction in annualized relapse rate at the 12-month follow-up after cladribine completion compared to the year prior to starting therapy (0.07 ± 0.25 vs. 0.82 ± 0.80, p < 0.001). Furthermore, patients with relapses during cladribine treatment were more likely to start new therapies, whereas older patients were less likely. The safety profile of cladribine was favorable, with lymphopenia being the primary registered adverse event.

Conclusions: This study provides insights into therapeutic choices and disease activity following cladribine treatment. It highlights cladribine's effectiveness in reducing relapse rates and disability progression, reaffirming its favorable safety profile. Real-world data, aligned with previous reports, draw attention to ocrelizumab and natalizumab as common choices after cladribine. However, larger, prospective studies for validation and a more comprehensive understanding of cladribine's long-term impact are necessary.

Keywords: cladribine; efficacy; multiple sclerosis; real‐world data; safety; treatment response.

Abstract

We report the case of a young man with sudden onset of diplopia after an upper respiratory tract infection. Based on the first radiological findings acute hemorrhagic leukoencephalitis, a variant of acute disseminated encephalomyelitis, was suspected and treatment with high dose intravenous dexamethasone was started but it was stopped for intolerance. The patient clinically worsened, developing gait instability, ataxia and ophthalmoplegia; brain MRI performed 20 days later showed severe progression of the disease with subependymal dissemination. After brain biopsy of the right temporal lesion the histological diagnosis was glioblastoma. These findings suggest that MRI features of acute hemorrhagic leukoencephalitis may dissimulate the diagnosis of diffuse glioma/glioblastoma. This case underscores the importance of considering diffuse glioma in the differential diagnosis of atypical signs and symptoms of acute hemorrhagic leukoencephalitis and underlines the relevant role of integrating neuroradiologic findings with neuropathology.

Keywords: Acute disseminated encephalomyelitis; acute hemorrhagic encephalitis; diffuse glioma; neuro-oncology.

No abstract available

Abstract

Background and objectives: The role of B cells in the pathogenic events leading to relapsing multiple sclerosis (R-MS) has only been recently elucidated. A pivotal step in defining this role has been provided by therapeutic efficacy of anti-CD20 monoclonal antibodies. Indeed, treatment with anti-CD20 can also alter number and function of other immune cells not directly expressing CD20 on their cell surface, whose activities can contribute to unknown aspects influencing therapeutic efficacy. We examined the phenotype and function of cytotoxic lymphocytes and Epstein-Barr virus (EBV)-specific immune responses in people with R-MS before and after ocrelizumab treatment.

Methods: In this prospective study, we collected blood samples from people with R-MS (n = 41) before and 6 and 12 months after initiating ocrelizumab to assess the immune phenotype and the indirect impact on cytotoxic functions of CD8+ T and NK cells. In addition, we evaluated the specific anti-EBV proliferative responses of both CD8+ T and NK lymphocytes as surrogate markers of anti-EBV activity.

Results: We observed that while ocrelizumab depleted circulating B cells, it also reduced the expression of activation and migratory markers on both CD8+ T and NK cells as well as their in vitro cytotoxic activity. A comparable pattern in the modulation of immune molecules by ocrelizumab was observed in cytotoxic cells even when patients with R-MS were divided into groups based on their prior disease-modifying treatment. These effects were accompanied by a significant and selective reduction of CD8+ T-cell proliferation in response to EBV antigenic peptides.

Discussion: Taken together, our findings suggest that ocrelizumab-while depleting B cells-affects the cytotoxic function of CD8+ and NK cells, whose reduced cross-activity against myelin antigens might also contribute to its therapeutic efficacy during MS.

Abstract

Background: in the early stages of Multiple Sclerosis (MS), initiating high-efficacy disease-modifying therapy (HE DMTs) may represent an optimal strategy for delaying neurological damage and long-term disease progression, especially in highly active MS patients (HAMS). Natalizumab (NAT) and Ocrelizumab (OCR) are recognized as HE DMTs with significant anti-inflammatory effects. This study investigates NEDA-3 achievement in treatment-naïve HAMS patients receiving NAT or OCR over three years.

Methods: we retrospectively enrolled treatment-naïve HAMS patients undergoing NAT or OCR, collecting demographic, clinical, and instrumental data before and after treatment initiation to compare with propensity score analysis disease activity, time to disability worsening, and NEDA-3 achievement.

Results: we recruited 281 HAMS patients with a mean age of 32.7 years (SD 10.33), treated with NAT (157) or OCR (124). After three years, the Kaplan-Meier probability of achieving NEDA-3 was 66.0 % (95 % CI: 57.3 % - 76.0 %) with OCR and 68.2 % (95 % CI: 59.9 % - 77.7 %) with NAT without significant differences between the two groups (p = 0.27) DISCUSSION AND CONCLUSION: starting HE DMT with monoclonal antibodies for HAMS could achieve NEDA-3 in a high percentage of patients without differences between NAT or OCR.

Keywords: High-efficacy disease-modifying therapy (HE DMTs); Highly active MS patients (HAMS); Multiple sclerosis; NEDA-3; Natalizumab; Ocrelizumab.

Abstract

Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by demyelination in the central nervous system (CNS), affecting individuals globally. The pathological mechanisms underlying MS remain unclear, but current evidence suggests that inflammation and immune dysfunction play a critical role in the pathogenesis of MS disease. Adipose tissue (AT) is a dynamic multifunctional organ involved in various immune diseases, including MS, due to its endocrine function and the secretion of adipokines, which can influence inflammation and immune responses. Physical activity represents an efficacious non-pharmacological strategy for the management of a spectrum of conditions that not only improves inflammatory and immune functions but also directly affects the status and function of AT. Additionally, the exploration of nutritional supplementation represents an important field of MS research aimed at enhancing clinical symptoms and is closely tied to the regulation of metabolic responses, including adipokine secretion. This review, therefore, aims to elucidate the intricate relationship between lifestyle and MS by providing an overview of the latest published data about the involvement of AT and the main adipokines, such as adiponectin, leptin, and tumor necrosis factor α (TNFα) in the pathogenesis of MS. Furthermore, we explore whether physical activity and dietary management could serve as useful strategies to improve the quality of life of MS patients.

Keywords: adipokines; adipose tissue; diet; multiple sclerosis; nutritional supplements; physical activity.

Abstract

Background: Neuromyelitis optica spectrum disorder (NMOSD) is a severely disabling autoimmune disease that predominantly impacts the optic nerves and spinal cord. It is often linked to immunoglobulin G (IgG) antibodies targeting the aquaporin-4 water channel (AQP4-IgG). Rituximab, which depletes CD20-positive B cells, is effective in reducing the frequency of NMOSD relapses. The objective of this retrospective, 5-year observational study was to evaluate the effectiveness and safety of rituximab in patients with AQP4-IgG-positive NMOSD.

Methods: We conducted a multicenter, retrospective study using prospectively collected data from 23 multiple sclerosis (MS) and NMOSD centers (22 in Italy, 1 in Switzerland). The study cohort included patients with AQP4-IgG-positive NMOSD who had completed rituximab induction therapy, with data collected up to May 2024. Two maintenance strategies were used-fixed 6-monthly infusions or reinfusions guided by flow cytometry-on the basis of CD19+ or CD27+ memory B-cell repopulation thresholds. Clinical outcomes included annualized relapse rate (ARR), time to first relapse (TTFR), and Expanded Disability Status Scale (EDSS) worsening, which was assessed both overall and between relapses to indirectly evaluate the possibility of inter-attack disability progression. Safety outcomes encompassed infusion-related reactions and adverse events.

Results: A total of 138 patients were analyzed. ARR significantly decreased from 1.54 (95% confidence interval (CI) 1.34-1.75) before rituximab to 0.15 (95% CI 0.12-0.19) over the 5-year follow-up. Approximately 33% of patients experienced at least one relapse during treatment, after a median time of 5.21 months. Higher pre-rituximab relapse rates were associated with shorter TTFR. Subtle increases of 0.5-1 points in EDSS between relapses were observed in one third of patients. Mild infections were common, and 21% of patients experienced infusion-related reactions. In addition, six patients developed malignancies.

Conclusions: Over 5 years, rituximab consistently reduced the incidence of relapses in patients with NMOSD, though 33% of them still experienced a relapse during this period, generally within the first 6 months of treatment. No unexpected adverse events were identified. While safety monitoring remains crucial, further studies are needed to better understand rituximab's impact on NMOSD management.

Abstract

Background: Evidence on the impact of dimethyl fumarate (DMF) during pregnancy in women with multiple sclerosis (MS) is limited.

Objectives: To investigate disease activity and pregnancy outcomes in a retrospective cohort of women exposed to DMF in early pregnancy.

Methods: Women discontinuing DMF after pregnancy confirmation were identified from 29 Italian MS Centers. Disease activity 12 months before conception, during pregnancy, and 12 months postpartum were recorded, exploring reactivation predictors. Pregnancy and fetal outcomes were assessed.

Results: The study analyzed 137 pregnancies (12 pregnancy losses, 125 live births) from 137 women (mean age 32.9 ± 4.7 years), discontinuing DMF within a median (interquartile range (IQR)) interval of 4.9 (3.7-5.7) weeks from conception. In live birth pregnancies, annualized relapse rate (ARR) significantly decreased during pregnancy (ARR = 0.07, 95% confidence interval (CI): 0.03-0.14, p = 0.021) compared to pre-conception (ARR = 0.21 (95% CI: 0.14-0.30)) and increased postpartum ((ARR = 0.22 (95% CI: 0.15-0.32), p = 0.006). Median time to first relapse (TTFR) was 3.16 (IQR: 1:87-5.42) months. Higher pre-conception relapse number (hazard ratio (HR) = 2.33, 95% CI: 1.08-5.02) and Expanded Disability Status Scale (EDSS; HR = 1.81, 95% CI: 1.17-2.74) were associated with shorter TTFR, while treatment resumption with longer TTFR (HR = 0.29, 95% CI: 0.11-0.74). Fetal outcomes were unaffected by DMF exposure.

Conclusion: DMF discontinuation does not increase relapse risk during pregnancy. Early therapy restart prevents postpartum relapses. Early DMF exposure shows no adverse fetal outcomes.

Keywords: Multiple sclerosis; dimethyl fumarate; pregnancy.

Abstract

Objectives: To evaluate the concordance between Google Maps® application (GM®) and clinical practice measurements of ambulatory function (e.g., Ambulation Score (AS) and respective Expanded Disability Status Scale (EDSS)) in people with multiple sclerosis (pwMS).

Materials and methods: This is a cross-sectional multicenter study. AS and EDSS were calculated using GM® and routine clinical methods; the correspondence between the two methods was assessed. A multinomial logistic model is investigated which demographic (age, sex) and clinical features (e.g., disease subtype, fatigue, depression) might have influenced discrepancies between the two methods.

Results: Two hundred forty-three pwMS were included; discrepancies in AS and in EDDS assessments between GM® and routine clinical methods were found in 81/243 (33.3%) and 74/243 (30.4%) pwMS, respectively. Progressive phenotype (odds ratio [OR] = 2.8; 95% confidence interval [CI] 1.1-7.11, p = 0.03), worse fatigue (OR = 1.03; 95% CI 1.01-1.06, p = 0.01), and more severe depression (OR = 1.1; 95% CI 1.04-1.17, p = 0.002) were associated with discrepancies between GM® and routine clinical scoring.

Conclusion: GM® could easily be used in a real-life clinical setting to calculate the AS and the related EDSS scores. GM® should be considered for validation in further clinical studies.

Keywords: Ambulatory disorders; Digital health; Google Maps; e-Health.