Giovanni Novi

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.

Background: The reason why some multiple sclerosis (MS) patients show disease activity after alemtuzumab (ALM) is still unclear, but ocrelizumab (OCR) could represent an interesting sequential therapeutic approach. Objectives: To investigate safety and efficacy of OCR in MS patients with disease activity after two ALM courses. Methods: Observational retrospective multi-centers Italian cohort study. Results: Seventy-two subjects were included. Mean follow-up (FU) was 2.4 (±1) years. Forty-five patients (62.5%) experienced at least one adverse event (AE), with infections accounting for 96.7% of cases. A reduction in total lymphocytes was observed between OCR start and 6 months FU, driven by BCD19+ lymphocytes depletion ( p < 0.001). Immunoglobulin M (IgM) levels decreased between OCR start and 6 months FU ( p < 0.001). At 2-year FU, relapse, magnetic resonance imaging (MRI) activity and disability worsening-free survival were 92.1%, 90.8%, and 89.2%. The evidence of inflammatory activity between the two ALM courses was associated with higher risk of relapse, MRI activity, and NEDA-3 status loss in relapsing-remitting multiple sclerosis (RRMS; p = 0.02, p = 0.05, p = 0.01, respectively). Conclusions: OCR after two ALM courses seemed to be safe and effective. Early IgM hypogammaglobulinemia occurred in a high proportion of patients. The evidence of inflammatory activity between ALM courses seemed to increase the risk of MS re-activation on OCR treatment.

Objectives: neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease mainly affecting optic nerves and the spinal cord. Due to the potentially irreversible tissue damage, prevention of relapses is of utmost importance. Methods: We describe the atypical clinical course and pathology results of a patient with anti-aquaporin-4 antibody (anti-AQP4-Ab)-associated NMOSD who developed aseptic meningitis followed by limbic-encephalitis-like presentation with extensive brain lesions upon treatment with rituximab and tocilizumab. Results: The patient developed subacute cognitive decline with magnetic resonance imaging (MRI) evidence of extensive brain white matter lesions. In the hypothesis of an opportunistic brain infection, she underwent brain biopsy of the temporal pole. Pathology results revealed typical NMOSD findings with complement activation, supporting the hypothesis of an atypical presentation of anti-AQP-Ab-associated NMOSD. Accordingly, treatment with the complement-targeting drug eculizumab was started, leading to a dramatic clinical and MRI improvement. Discussion: aseptic meningitis and limbic encephalitis could represent a rare phenotype of anti-AQP4-Ab-associated NMOSD.

Background and Objectives To evaluate the long-term safety and efficacy of tocilizumab (TCZ), a humanized anti–interleukin-6 receptor antibody in myelin oligodendrocyte glycoprotein–IgG–associated disease (MOGAD) and neuromyelitis optica spectrum disorders (NMOSD). Methods Annualized relapse rate (ARR), Expanded Disability Status Scale score, MRI, autoantibody titers, pain, and adverse events were retrospectively evaluated in 57 patients with MOGAD (n = 14), aquaporin-4 (AQP4)-IgG seropositive (n = 36), and seronegative NMOSD (n = 7; 12%), switched to TCZ from previous immunotherapies, particularly rituximab. Results Patients received TCZ for 23.8 months (median; interquartile range 13.0–51.1 months), with an IV dose of 8.0 mg/kg (median; range 6–12 mg/kg) every 31.6 days (mean; range 26–44 days). For MOGAD, the median ARR decreased from 1.75 (range 0.5–5) to 0 (range 0–0.9; p = 0.0011) under TCZ. A similar effect was seen for AQP4-IgG+ (ARR reduction from 1.5 [range 0–5] to 0 [range 0–4.2]; p < 0.001) and for seronegative NMOSD (from 3.0 [range 1.0–3.0] to 0.2 [range 0–2.0]; p = 0.031). During TCZ, 60% of all patients were relapse free (79% for MOGAD, 56% for AQP4-IgG+, and 43% for seronegative NMOSD). Disability follow-up indicated stabilization. MRI inflammatory activity decreased in MOGAD (p = 0.04; for the brain) and in AQP4-IgG+ NMOSD (p < 0.001; for the spinal cord). Chronic pain was unchanged. Regarding only patients treated with TCZ for at least 12 months (n = 44), ARR reductions were confirmed, including the subgroups of MOGAD (n = 11) and AQP4-IgG+ patients (n = 28). Similarly, in the group of patients treated with TCZ for at least 12 months, 59% of them were relapse free, with 73% for MOGAD, 57% for AQP4-IgG+, and 40% for patients with seronegative NMOSD. No severe or unexpected safety signals were observed. Add-on therapy showed no advantage compared with TCZ monotherapy. Discussion This study provides Class III evidence that long-term TCZ therapy is safe and reduces relapse probability in MOGAD and AQP4-IgG+ NMOSD.

Objective We wanted to evaluate efficacy on inflammatory parameters of rituximab (RTX)-personalized reinfusion scheme using a memory B cell–based treatment regimen. Methods This is a prospective, uncontrolled, open-label study including patients with MS treated with RTX in 2 Italian MS units. All patients were treated with RTX induction, followed by maintenance infusion at the dosage of 375 mg/m², according to memory B cell repopulation (0.05% of peripheral-blood mononuclear cells [PBMCs] for the first 2 years, 0.1% of PBMC for the third year). MS activity was assessed as clinical or MRI activity. Results One hundred two patients were included in the analysis. Mean follow-up was 2.40 years (range 0.57–7.15 years). The annualized relapse rate (ARR) was 0.67 in the year before RTX start and decreased to 0.01 in the 3 years after RTX initiation (global ARR). The proportion of patient with MS activity (i.e., relapse or MRI activity) was 63.16% in the year before RTX start and decreased to 8.7% (0–6 months), 1.3% (6–12 months), 0% (12–24 months), and 0% (24–36 months). Annualized RTX infusion rates were 1.67 (95% confidence interval [CI]: 1.43–1.94), 0.76 (95% CI: 0.58–0.98), and 0.78 (95% CI: 0.52–1.12) for the first 3 years after RTX initiation, respectively. Patients were reinfused with a mean infusion interval of 367 days (range 181–839 days). Conclusion The results of this study show that the memory B cell–based RTX reinfusion protocol is able to reduce the mean number of RTX reinfusions with persistent reduction of disease activity. Classification of evidence This study provides Class IV evidence that for patients with MS, a memory B cell–based RTX reinfusion protocol can reduce the mean number of RTX reinfusions with persistent reduction of disease activity.

Background The importance of upper limb function in multiple sclerosis (MS) is increasingly recognized, especially for evaluating progressive patients with a reduced mobility. Two sensor‐engineered gloves able to quantitatively measure the timing of finger opposition movements was previously used to assess upper limb disability in MS. Aims of the study were: a)to confirm the association between glove parameters and standard measures of MS disability in a larger cohort; b)to assess the correlation with quantitative MRI and quality of life (QoL) measures and c)to determine if the glove‐derived parameters offer advantages over to the standard measure for assessing upper limb in MS, namely the Nine‐Hole Peg Test (9HPT). Methods 65 patients with MS stable under disease modifying treatment were evaluated at baseline by the glove, clinical examination (EDSS,SDMT,T25FW,9HPT), MRI evaluation and QoL questionnaires. Correlations between the glove parameters and clinical, MRI and QoL variables were assessed by the Spearman rank correlation coefficient. Results Glove parameters significantly differ between relapsing‐remitting and progressive MS patients, with similar or slightly higher correlations of the 9HPT with clinical variables. We found larger correlations of the QoL physical component with glove parameters than with 9HPT, and a significant correlation of its mental component with the glove parameters but not with 9HPT. Conclusion The study results, confirming previous findings and showing advantages over the 9HPT, encourage the investigation of the sensitivity to change of the glove‐derived parameters in a longitudinal setting.

Objective To establish cytometry profiles associated with disease stages and immunotherapy in MS. Methods Demographic/clinical data and peripheral blood samples were collected from 227 patients with MS and 82 sex- and age-matched healthy controls (HCs) enrolled in a cross-sectional study at 4 European MS centers (Spain, Italy, Germany, and Norway). Flow cytometry of isolated peripheral blood mononuclear cells was performed in each center using specifically prepared antibody-cocktail Lyotubes; data analysis was centralized at the Genoa center. Differences in immune cell subsets were assessed between groups of untreated patients with relapsing-remitting or progressive MS (RRMS or PMS) and HCs and between groups of patients with RRMS taking 6 commonly used disease-modifying drugs. Results In untreated patients with MS, significantly higher frequencies of Th17 cells in the RRMS population compared with HC and lower frequencies of B-memory/B-regulatory cells as well as higher percentages of B-mature cells in patients with PMS compared with HCs emerged. Overall, the greatest deviation in immunophenotype in MS was observed by treatment rather than disease course, with the strongest impact found in fingolimod-treated patients. Fingolimod induced a decrease in total CD4⁺ T cells and in B-mature and B-memory cells and increases in CD4⁺ and CD8⁺ T-regulatory and B-regulatory cells. Conclusions Our highly standardized, multisite cytomics data provide further understanding of treatment impact on MS immunophenotype and could pave the way toward monitoring immune cells to help clinical management of MS individuals.