Hypogammaglobulinaemia during rituximab treatment in multiple sclerosis: A Swedish cohort study.

BACKGROUND AND PURPOSE: Mechanisms behind hypogammaglobulinaemia during rituximab treatment are poorly understood. METHODS: In this register-based multi-centre retrospective cohort study of multiple sclerosis (MS) patients in Sweden, 2745 patients from six participating Swedish MS centres were identified via the Swedish MS registry and included between 14 March 2008 and 25 January 2021. The exposure was treatment with at least one dose of rituximab for MS or clinically isolated syndrome, including data on treatment duration and doses. The degree of yearly decrease in immunoglobulin G (IgG) and immunoglobulin M (IgM) levels was evaluated. RESULTS: The mean decrease in IgG was 0.27 (95% confidence interval 0.17-0.36) g/L per year on rituximab treatment, slightly less in older patients, and without significant difference between sexes. IgG or IgM below the lower limit of normal (<6.7 or <0.27 g/L) was observed in 8.8% and 8.3% of patients, respectively, as nadir measurements. Six out of 2745 patients (0.2%) developed severe hypogammaglobulinaemia (IgG below 4.0 g/L) during the study period. Time on rituximab and accumulated dose were the main predictors for IgG decrease. Previous treatment with fingolimod and natalizumab, but not teriflunomide, dimethyl fumarate, interferons or glatiramer acetate, were significantly associated with lower baseline IgG levels by 0.80-1.03 g/L, compared with treatment-naïve patients. Switching from dimethyl fumarate or interferons was associated with an additional IgG decline of 0.14-0.19 g/L per year, compared to untreated. CONCLUSIONS: Accumulated dose and time on rituximab treatment are associated with a modest but significant decline in immunoglobulin levels. Previous MS therapies may influence additional IgG decline.

Safety and efficacy of rituximab versus dimethyl fumarate in patients with relapsing-remitting multiple sclerosis or clinically isolated syndrome in Sweden: a rater-blinded, phase 3, randomised controlled trial.

BACKGROUND: B-cell depleting therapies are highly efficacious in relapsing-remitting multiple sclerosis but one such therapy, rituximab, is not approved for multiple sclerosis and no phase 3 trial data are available. We therefore examined the safety and efficacy of rituximab compared with dimethyl fumarate in patients with relapsing-remitting multiple sclerosis to obtain data that might allow inclusion of rituximab in treatment guidelines. METHODS: RIFUND-MS was a multicentre, rater-blinded, active-comparator, phase 3, randomised controlled trial done at 17 Swedish university and community hospitals. Key inclusion criteria for participants were: age 18-50 years; relapsing-remitting multiple sclerosis or clinically isolated syndrome according to prevailing McDonald criteria; 10 years or less since diagnosis; untreated or only exposed to interferons or glatiramer acetate; and with clinical or neuroradiological disease activity in the past year. Patients were automatically randomly assigned (1:1) by the treating physician using a randomisation module in the Swedish multiple sclerosis registry, without stratification, to oral dimethyl fumarate 240 mg twice daily or to intravenous rituximab 1000 mg followed by 500 mg every 6 months. Relapse evaluation, Expanded Disability Status Scale rating, and assessment of MRI scans were done by examining physicians and radiologists masked to treatment allocation. The primary outcome was the proportion of patients with at least one relapse (defined as subacute onset of new or worsening neurological symptoms compatible with multiple sclerosis with a duration of more than 24 h and preceded by at least 30 days of clinical stability), assessed in an intention-to-treat analysis using log-binomial regression with robust standard errors. This trial is registered at ClinicalTrials.gov, NCT02746744. FINDINGS: Between July 1, 2016, and Dec 18, 2018, 322 patients were screened for eligibility, 200 of whom were randomly assigned to a treatment group (100 assigned to rituximab and 100 assigned to dimethyl fumarate). The last patient completed 24-month follow-up on April 21, 2021. 98 patients in the rituximab group and 97 patients in the dimethyl fumarate group were eligible for the primary outcome analysis. Three (3%) patients in the rituximab group and 16 (16%) patients in the dimethyl fumarate group had a protocol-defined relapse during the trial, corresponding to a risk ratio of 0·19 (95% CI 0·06-0·62; p=0·0060). Infusion reactions (105 events [40·9 per 100 patient-years]) in the rituximab group and gastrointestinal reactions (65 events [47·4 per 100 patient-years]) and flush (65 events [47·4 per 100 patient-years]) in the dimethyl fumarate group were the most prevalent adverse events. There were no safety concerns. INTERPRETATION: RIFUND-MS provides evidence that rituximab given as 1000 mg followed by 500 mg every 6 months is superior to dimethyl fumarate in preventing relapses over 24 months in patients with early relapsing-remitting multiple sclerosis. Health economic and long-term safety studies of rituximab in patients with multiple sclerosis are needed. FUNDING: Swedish Research Council.

Comparison of plasma and cerebrospinal fluid neurofilament light in a multiple sclerosis trial.

OBJECTIVE: The main objective of this study was to evaluate the axonal component neurofilament light protein (NFL) in plasma and cerebrospinal fluid (CSF) as an outcome measure in a clinical trial on disease-modifying treatments in multiple sclerosis. MATERIALS AND METHODS: Seventy-five patients with clinically stable relapsing-remitting multiple sclerosis (RRMS) participating in the clinical trial "Switch-To RItuXimab in MS" (STRIX-MS) were switched to rituximab from first-line injectable therapy and then followed up for 2 years. Thirty patients from the extension trial (STRIX-MS extension), accepting repeated lumbar punctures, were followed up for an additional 3 years. Plasma and CSF samples were collected yearly during the follow-up. NFL concentration in plasma was measured by an in-house NF-light assay on the Simoa platform with a Homebrew kit. NFL concentration in CSF was measured by sandwich ELISA. RESULTS: The mean levels of NFL, in both CSF and plasma, were low. The reduction of CSF-NFL was 25% during the first year of follow-up (from a mean of 471 [SD 393] to 354 [SD 174] pg/mL; P = 0.006) and was statistically significant. The corresponding reduction in plasma NFL was 18% (from 9.73 [SD 7.04] to 7.94 [SD 3.10] pg/mL; P = 0.055) and did not reach statistical significance. CONCLUSION: This study indicates that NFL in plasma is less sensitive as an endpoint in group comparisons than NFL in CSF. Given that plasma NFL is far easier to access, it is a promising and awaited method but further studies are needed to optimize the use in clinical trials.

Immunological profile in cerebrospinal fluid of patients with multiple sclerosis after treatment switch to rituximab and compared with healthy controls.

OBJECTIVE: To investigate changes in the cerebrospinal fluid (CSF) immunological profile after treatment switch from first-line injectables to rituximab in patients with relapsing-remitting MS (RRMS), and to compare the profile in MS patients with healthy controls (HC). METHOD: Cerebrospinal fluid from 70 patients with clinically stable RRMS and 55 HC was analysed by a multiplex electrochemiluminescence method for a broad panel of cytokines and immunoactive substances before, and over a two-year period after, treatment switch to rituximab. After quality assessment of data, using a predefined algorithm, 14 analytes were included in the final analysis. RESULTS: Ten of the 14 analytes differed significantly in MS patients compared with HC at baseline. Levels of IP-10 (CXCL10), IL-12/23p40, IL-6, sVCAM1, IL-15, sICAM1 and IL-8 (CXCL8) decreased significantly after treatment switch to rituximab. The cytokines IP-10 and IL-12/IL-23p40 displayed the largest difference versus HC at baseline and also the largest relative reduction after therapy switch to rituximab. CONCLUSION: We found significant changes in the immunological profile after therapy switch to rituximab in RRMS in the direction towards the values of HC. IP-10 and IL12/IL-23p40 deserve further studies as part of the immunopathogenesis of MS as well as for the mode of action of rituximab in MS.

Improved treatment satisfaction after switching therapy to rituximab in relapsing-remitting MS.

OBJECTIVE: New disease-modifying treatment strategies in multiple sclerosis offer possibilities for individualised treatment. In this study, we evaluated patient-reported outcome measures before and after a switch in therapy from first-line injectable treatments to rituximab. METHOD: A total of 75 patients with clinically stable relapsing-remitting multiple sclerosis (RRMS) receiving ongoing first-line injectable treatment at three Swedish centres had their treatment switched to rituximab in this open-label phase II multicentre study. Assessment of treatment satisfaction, patient-perceived impact of the disease on daily life, fatigue, cognitive symptoms and disease progression was performed 3 months before and at the time of the treatment shift and then for a subsequent 2-year period. RESULTS: The overall treatment satisfaction rating improved significantly from a mean of 4.8 (scale range: 1-7), while on injectable therapies, to a mean of 6.3 after 1 year of rituximab treatment ( p < 0.001). This improvement was sustained after 2 years. There was no significant change in scores for patient-perceived impact of disease, fatigue or disease progression. CONCLUSION: A shift in therapy from first-line injectables to rituximab in a cohort of clinically stable RRMS patients was followed by improved treatment satisfaction. This is clinically relevant as it may influence long-term adherence to immunomodulating therapy.

Reduced inflammation in relapsing-remitting multiple sclerosis after therapy switch to rituximab.

OBJECTIVE: To describe the effects of switching treatment from ongoing first-line injectable therapies to rituximab on inflammatory activity measured by MRI and levels of CSF neurofilament light chain (CSF-NFL) in a cohort of patients with clinically stable relapsing-remitting multiple sclerosis (RRMS). METHOD: Seventy-five patients with clinically stable RRMS treated with the first-line injectables interferon-ß (IFN-ß) and glatiramer acetate (GA) at 3 Swedish centers were switched to rituximab in this open-label phase II multicenter study. After a run-in period of 3 months, 2 IV doses of 1,000 mg rituximab were given 2 weeks apart followed by repeated clinical assessment, MRI, and CSF-NFL for 24 months. RESULTS: The mean cumulated number of gadolinium-enhancing lesions per patient at months 3 and 6 after treatment shift to rituximab was reduced compared to the run-in period (0.028 vs 0.36, p = 0.029). During the first year after treatment shift, the mean number of new or enlarged T2 lesions per patient was reduced (0.01 vs 0.28, p = 0.004) and mean CSF-NFL levels were reduced by 21% (p = 0.01). CONCLUSIONS: For patients with RRMS, a treatment switch from IFN or GA to rituximab is associated with reduced inflammatory activity measured by MRI and CSF-NFL. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that rituximab has an equal or superior effect in reducing inflammatory activity in RRMS measured by MRI and CSF-NFL compared to first-line injectables during the first year after treatment shift.

Pharmacokinetics of topiramate during pregnancy.

PURPOSE: To study the effects of pregnancy on plasma concentrations of topiramate (TPM). METHODS: An established routine fluorescence polarization immunoassay (FPIA) method was used to determine TPM concentrations in 15 women with epilepsy treated with TPM during altogether 17 pregnancies. RESULTS: In 10 pregnancies, where samples were available from all three trimesters, the mean TPM dose/concentration ratio (D/C-ratio) was significantly higher than outside pregnancy baseline value 37.3 L/day (+/-15.9), during the 2nd, 67.5L/day (+/-23.4), and the 3rd trimester, 65.1L/day (+/-30.4), but not during the 1st, 49.4 L/day (+/-29.4). Including seven additional pregnancies enrolled late with data only from the 3rd trimester, the mean D/C-ratio during the 3rd trimester was 67.4 L/day (+/-27.5) compared to baseline, 38.8L/day (+/-18.0), an average increase by 71.8%. There was a pronounced intra-individual variability in alterations in D/C-ratios during pregnancies. CONCLUSIONS: Our data show a significant pregnancy-related increase in D/C-ratios of TPM suggesting that therapeutic drug monitoring might be of value.