Tailoring B cell depletion therapy in MS according to memory B cell monitoring.

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.

Treatment of multiple sclerosis with rituximab: A multicentric Italian-Swiss experience.

BACKGROUND: Rituximab, an anti-CD20 monoclonal antibody leading to B lymphocyte depletion, is increasingly used as an off-label treatment option for multiple sclerosis (MS). OBJECTIVE: To investigate the effectiveness and safety of rituximab in relapsing-remitting (RR) and progressive MS. METHODS: This is a multicenter, retrospective study on consecutive MS patients treated off-label with rituximab in 22 Italian and 1 Swiss MS centers. Relapse rate, time to first relapse, Expanded Disability Status Scale (EDSS) progression, incidence of adverse events, and radiological outcomes from 2009 to 2019 were analyzed. RESULTS: A total of 355/451 enrolled subjects had at least one follow-up visit and were included in the outcome analysis. Annualized relapse rate significantly decreases after rituximab initiation versus the pre-rituximab start year in RRMS (from 0.86 to 0.09, p < .0001) and in secondary-progressive (SP) MS (from 0.34 to 0.06, p < .0001) and had a slight decrease in primary-progressive (PP) MS patients (from 0.12 to 0.07, p = 0.45). After 3 years from rituximab start, the proportion of patients with a confirmed EDSS progression was 14.6% in the RRMS group, 24.7% in the SPMS group, and 41.5% in the PPMS group. No major safety concerns arose. CONCLUSION: Consistently with other observational studies, our data show effectiveness of rituximab in reducing disease activity in patients with MS.

Efficacy of different rituximab therapeutic strategies in patients with neuromyelitis optica spectrum disorders.

OBJECTIVE: To evaluate disease activity according to rituximab (RTX) induction and maintenance regimens in a multicenter real-life dataset of NMOSD patients. METHODS: This is an observational-retrospective multicentre study including patients with NMOSD treated with RTX in 21 Italian and 1 Swiss centers. Demographics, relapse rate and adverse events over the follow-up were summarized taking into account induction strategy (two-1 g infusions at a 15-day interval (IND-A) vs. 375 mg/m2/week infusions for one month (IND-B)) and maintenance therapy (regimen A (M-A) with fixed time-points infusions vs. regimen B (M-B) based on cytofluorimetric driven reinfusion regimens, the least further subdivided according to CD19+ B cells (M-B1) or CD27+ memory B cells (M-B2) monitoring). RESULTS: 131 subjects were enrolled, 127 patients completed the induction regimen and 119 patients had at least one follow-up visit and were included in the outcome analysis. Median follow-up was 1.7 years (range 0.1-11.6). Annualized relapse rate (ARR) was 1.7 in the year before RTX start and decreased to 0.19 during the follow-up. Both ARR and Time to first relapse (TTFR) analysis showed a trend toward an increased disease activity for IND-B and M-A. No patients with MT-B2 experienced relapses during the follow-up. Number of relapses in the year before RTX initiation and having received a previous treatment were significantly associated with higher ARR and reduced TTFR in the multivariate analysis. INTERPRETATION: We confirm RTX efficacy in NMOSD patients. Use of specific induction and maintenance protocols is warranted in order to foster RTX efficacy and to reduce costs and side effects.

Expanded disability status scale progression assessment heterogeneity in multiple sclerosis according to geographical areas.

Using placebo data from 3 randomized multiple sclerosis (MS) trials with uniform inclusion criteria, we investigated heterogeneity of Expanded Disability Status Scale (EDSS) progression by geographical areas. Our analysis revealed a significantly lower EDSS progression in Eastern European countries (10.8%) compared with Western Europe (13.1%) or the USA/Canada (21.4%, p < 0.001); EDSS improvement behaved the same way. This heterogeneity is not explained by differences of baseline variables. No differences were detected on more easily quantifiable measures, the Timed 25-Foot Walk or the Multiple Sclerosis Functional Composite. At a time when disease progression represents the target for future interventions in MS, establishment of more quantitative and objective outcomes remains a key priority of MS research. Ann Neurol 2018;84:621-625.

Long-term impact of interferon or Glatiramer acetate in multiple sclerosis: A systematic review and meta-analysis.

BACKGROUND: In recent years the impact of disease-modifying drugs on long-term progression in multiple sclerosis (MS) was assessed both in observational studies and in extension of randomized controlled trial (RCT). Aim of this work was to quantitatively summarize by a meta-analysis the long-term impact of immunomodulatory drugs (Interferon-Beta (IFN-ß) or Glatiramer Acetate (GA)) in relapsing-remitting (RR) MS patients. METHODS: We collected all published observational studies reporting the long-term efficacy of IFN-ß or GA in RRMS patients. The primary outcome was the treatment effect on progression to a sustained EDSS score of 6 or to the Secondary Progressive (SP) phase. A non-parametric approach was adopted to test the overall treatment effect significance, while a random effect model was used to obtain a pooled quantitative estimate of the treatment benefit, in terms of hazard-ratios (HR) or Relative Risks, with their 95% confidence interval (CI). RESULTS: Fourteen studies, on a total of 13,238 RRMS patients, were included in the meta-analysis. All studies but two reported a consistent effect of immunomodulatory treatment on long-term disease progression; the pooled effect on progression to EDSS 6 or SP was significant (p<0.01) when tested by the non-parametric test. The quantitative estimate of the treatment effect in reducing progression to EDSS 6 in the subset of studies reporting this outcome was HRpooled=0.49 (95% CI: 0.34-0.69), p<0.001. CONCLUSIONS: Treatment with immunomodulators seems to reduce long-term probability of disability progression. Additional well-designed observational studies could help to confirm these findings.