Effect of Prior Treatment With Fingolimod on Early and Late Response to Rituximab/Ocrelizumab in Patients With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Real-life studies noted that the risk of disease activity in multiple sclerosis (MS) after switching to rituximab (RTX) or ocrelizumab (OCR) may be unequal depending on prior disease-modifying therapy (DMT), with a higher risk associated with fingolimod (FING). METHODS: We performed a retrospective analysis of a structured prospective data collection including all consecutive patients with relapsing MS who were prescribed RTX/OCR in the MS center of Marseille. Cox proportional hazards models were applied to clinical and MRI outcomes. RESULTS: We included 321 patients with a median (interquartile range [IQR]) follow-up of 3.5 years (1.5-5) after RTX/OCR initiation. At the first RTX/OCR infusion, the mean (SD) age of patients was 37 (10) years, and the median (IQR) disease duration was 8 years (3-15): 68 patients did not receive treatment before RTX/OCR and 108 switched from FING, 47 from low efficacy therapy, and 98 from natalizumab. For statistical analysis, the group "FING" was divided into "short-FING" and "long-FING" groups according to the median value of the group's washout period (27 days). On Cox proportional hazards analysis, for only the "long-FING" group, the risk of relapse within the first 6 months of RTX/OCR was increased as compared with patients without previous DMT (hazard ratio [HR]: 8.78; 95% CI 1.72-44.86; p < 0.01). Previous DMT and washout period duration of FING had no effect on B-cell levels at 6 months. Beyond the first 6 months of RTX/OCR, age <40 years was associated with increased risk of relapse (HR: 3.93; 95% CI 1.30-11.89; p = 0.01), male sex with increased risk of new T2 lesions (HR: 2.26; 95% CI 1.08-4.74; p = 0.03), and EDSS ≥2 with increased risk of disability accumulation (HR: 3.01; 95% CI 1.34-6.74; p < 0.01). Previous DMT had no effect on the effectiveness of RTX/OCR beyond 6 months after initiation. DISCUSSION: For patients switching from FING to RTX/OCR, the risk of disease reactivation within the first 6 months of treatment was increased as compared with patients with other DMT or no previous DMT only when the washout period exceeded 26 days. Neither FING nor other previous DMT reduced the effectiveness of RTX/OCR beyond the first 6 months of treatment.

Efficacy of Rituximab Outlasts B-Cell Repopulation in Multiple Sclerosis: Time to Rethink Dosing?

BACKGROUND AND OBJECTIVES: Patients with multiple sclerosis (PwMS) receiving extended dosing of rituximab (RTX) have exhibited no return of disease activity, which suggests that maintenance of deep depletion of circulating B cells is not necessary to maintain the efficacy of RTX in MS. METHODS: This was a prospective monocentric observational study including all consecutive PwMS who started or continued RTX after 2019, when the medical staff decided to extend the dosing interval up to 24 months for all patients. Circulating B-cell subsets were monitored regularly and systematically in case of relapse. The first extended interval was analyzed. RESULTS: We included 236 PwMS (81% with relapsing-remitting MS; mean [SD] age 43 [12] years; median [range] EDSS score 4 [0-8]; mean relapse rate during the year before RTX start 1.09 [0.99]; 41.5% with MRI activity). The median number of RTX infusions before extension was 4 (1-13). At the time of the analysis, the median delay in dosing was 17 months (8-39); the median proportion of circulating CD19+ B cells was 7% (0-25) of total lymphocytes and that of CD27+ memory B cells was 4% (0-16) of total B cells. The mean annual relapse rate did not differ before and after the extension: 0.03 (0.5) and 0.04 (0.15) (p = 0.51). Similarly, annual relapse rates did not differ before and after extension in patients with EDSS score ≤3 (n = 79) or disease duration ≤5 years (n = 71) at RTX onset. During the "extended dosing" period, MRI demonstrated no lesion accrual in 228 of the 236 patients (97%). Five patients experienced clinical relapse, which was confirmed by MRI. In these patients, the level of B-cell subset reconstitution at the time of the relapse did not differ from that for patients with the same extension window. DISCUSSION: The efficacy of RTX outlasted substantial reconstitution of circulating B cells in PwMS, which suggests that renewal of the immune system underlies the prolonged effect of RTX in MS. These findings suggest that extended interval dosing of RTX that leads to a significant reconstitution of circulating B cells is safe in PwMS, could reduce the risk of infection, and could improve vaccine efficacy.

Hypogammaglobulinemia and Infections in Patients With Multiple Sclerosis Treated With Rituximab.

BACKGROUND AND OBJECTIVES: To determine the frequency of hypogammaglobulinemia and infections in patients with multiple sclerosis (PwMS) receiving rituximab (RTX). METHODS: This prospective observational study included all consecutive PwMS receiving RTX at the university hospital of Marseille, France, between 2015 and 2020. Patient visits occurred at least every 6 months. RESULTS: We included 188 patients (151 with relapsing-remitting MS; the mean age was 43.4 years [SD 12.9], median disease duration 10 years [range 0-36], median Expanded Disability Status Scale 5 [range 0-8], median follow-up 3.5 years [range 1-5.8], and median number of RTX infusions 5 [range 1-9]). Overall, 317 symptomatic infections and 13 severe infections occurred in 133 of 188 (70.7%) and 11 of 188 (5.9%) patients, respectively. After 4 years, 24.4% of patients (95% CI 18.0-33.1) were free of any infection and 92.0% (95% CI 87.1-97.1) had not experienced a severe infection. At RTX onset, the immunoglobulin G (IgG) level was abnormal in 32 of 188 (17%) patients. After RTX, IgG level was <7, <6, <4 and <2 g/L for 83 (44%), 44 (23.4%), 8 (4.2%) and 1 (0.53%) patients, respectively. The risk of infection was associated with reduced IgG levels (multivariate Cox proportional hazards hazard ratio [HR] = 0.86, 95% CI 0.75-0.98, p = 0.03). The risk of reduced IgG level <6 g/L increased with age (HR = 1.36, 95% CI 1.05-1.75, p = 0.01). DISCUSSION: In PwMS receiving RTX, reduced IgG level was frequent and interacted with the risk of infection.

Extending rituximab dosing intervals in patients with MS during the COVID-19 pandemic and beyond?

OBJECTIVE: To evaluate disease activity in patients with relapsing-remitting MS (RRMS) receiving rituximab with an extended dosing interval. METHODS: In the context of COVID-19 pandemic, this was an interim analysis of an ongoing prospective observational study of patients who were stable on rituximab for at least 6 months and who had a planned extended dosing interval of 24 months. Only data for patients with active RRMS before rituximab were analyzed. RESULTS: Among 177 patients receiving rituximab, 33 had RRMS and MRI activity before rituximab and at least 8 months of follow-up after the last infusion. The mean (SD) age was 40 (14) years, 25 were females, the mean disease duration was 10 (6.8) years, the mean annual relapse rate (ARR) before rituximab was 1.7 (1.3), and the median Expanded Disability Status Scale (EDSS) score before rituximab was 4.5 (1-7). Before extended dosing, when rituximab was infused every 6 months, the mean (SD) ARR decreased to 0.04 (0.1) (p < 0.0001) and the EDSS score to 4 (0-7) (p = 0.04). At the time of this analysis, the median follow-up since the last infusion was 11 (8-31) months. No patient showed relapse or disability progression. In total, 30 patients had at least 1 MRI performed since the last infusion (median time between the last MRI and the last infusion 10 [8-31] months). No MRI showed activity. The CD19+ cell proportion was >1% for 10 of 25 patients at the last count (median time 8 [6-25] months). CONCLUSIONS: An extended dosing interval for rituximab for patients with stable MS during the COVID-19 pandemic may be associated with a low risk of disease activity.