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.

[Ketamine use in outpatients: What can we learn from current practices?] / Utilisation de la kétamine chez les patients ambulatoires : que pouvons-nous apprendre des pratiques actuelles ?

INTRODUCTION: Two off-label use of ketamine are framed by recommendations: in intractable pain in palliative situations or in postoperative pain. Ketamine is used in hospital but can also be used outside hospital with dispensations by hospital pharmacy to outpatients. Few data are available on ketamine use outside hospital. In this context, the French Addictovigilance Network has set up a study with hospital pharmacies. MATERIALS AND METHODS: This survey assesses ketamine dispensations from 1 January to 30 April 2019, for patients who have an administration of ketamine outside hospital. RESULTS: Sixty-five (65) hospital pharmacies have dispensed ketamine for 553 patients. Ketamine was indicated within non-palliative care in 86% of cases. Most of non-cancer pain were in fibromyalgia (44%) and neuropathic pain (29%). During the 4-month monitoring period, 1352 dispensations were analysed. The frequency of administration is daily in 91% of cases within palliative care whereas it is much more diverse within non-palliative care (33% daily, more than 15 different frequency in fibromyalgia). Within palliative care, ketamine is most administered intravenously or by Patient Controlled Analgesia or syringe pump (78% of cases) whereas in non-palliative care, ketamine is most used subcutaneously (44%), orally (32%) or both subcutaneously and orally (20%). A large number of ampoules could be dispensed (more than 30 ampoules for 10% of dispensations). CONCLUSION: These data highlighted that recommendation in pain are not respected because most of ketamine is used within non-palliative care context and it should be noted a great heterogeneity of practice. This study underlines the urgency of targeted and clear information on certain off-label uses of ketamine for which no robust clinical studies are available and for which the risk of health complications like psychiatric (addiction), urologic and hepatologic complications is proven.