Project description:We conducted a retrospective cohort study in Kaiser Permanente Southern California from 1 January 2020 to 30 September 2020. We found that rituximab-treated persons with multiple sclerosis (pwMS, n = 1895) were more likely be hospitalized (n = 8, 33.3%), but not die (n = 0) from COVID-19, compared to the 4.81 million non-MS population (5.8% and 1.4%, respectively). Time in months (adjusted OR = 0.32, 95% CI = 0.15-0.69, p = 0.0033) and receiving 1000 mg compared to lower doses at last infusion (adjusted OR = 6.28, 95% CI = 1.38-28.5, p = 0.0173) were independent predictors of COVID-19 severity. Rituximab-treated pwMS should be counseled to take extra precautions in the 5 months following each infusion. Using extended dosing intervals and lower doses could be considered.
Project description:Over recent years increased MS incidence, primarily in women, has been reported. We recently reported an unexpectedly high MS prevalence of 189/100,000 in Sweden. In the present study we estimated the nationwide age- and gender-specific MS incidence and the sex ratio in Sweden between 2001 and 2008. MS patients were identified by linking two nationwide health data registers, and the Swedish population register. The earliest registered date of MS diagnosis was determined. By logistic regression, the probability of the date of MS diagnosis being within the incidence period, depending on age and time was estimated for a subset of patients and applied to other patients. By Poisson regression, the hazard functions for the incidence of MS diagnosis were estimated. The expected number of MS patients was 7,361.4. The incidence in the average population of 9,054,658 was 10.2 per 100,000 person-years, and 6.2 and 14.0 per 100,000 person-years for men and women, respectively. The crude female to male ratio was 2.26. No increase of incidence or change of sex ratio was observed from 2001 to 2008. In conclusion, the average MS incidence in Sweden from 2001 to 2008 was 10.2 per 100.000, which was considerably higher than previous regional Swedish estimates of 4.3-6.4. No increase of female to male ratio of MS during the study period was observed. We provide supplementary data that can be used as tools for examining excess MS risk in different study materials.
Project description:In the last decades, evidence suggesting the direct or indirect involvement of B cells on multiple sclerosis (MS) pathogenesis has accumulated. The increased amount of data on the efficacy and safety of B-cell-depleting therapies from several studies has suggested the addition of these drugs as treatment options to the current armamentarium of disease modifying therapies (DMTs) for MS. Particularly, rituximab (RTX), a chimeric monoclonal antibody directed at CD20 positive B lymphocytes resulting in cell-mediated apoptosis, has been demonstrated to reduce inflammatory activity, incidence of relapses and new brain lesions on magnetic resonance imaging (MRI) in patients with relapsing-remitting MS (RRMS). Additional evidence also demonstrated that patients with progressive MS (PMS) may benefit from RTX, which also showed to be well tolerated, with acceptable safety risks and favorable cost-effectiveness profile.Despite these encouraging results, RTX is currently approved for non-Hodgkin's lymphoma, chronic lymphocytic leukemia, several forms of vasculitis and rheumatoid arthritis, while it can only be administered off-label for MS treatment. Between Northern European countries exist different rules for using not licensed drug for treating MS. The Sweden MS register reports a high rate (53.5%) of off-label RTX prescriptions in relation to other annually started DMTs to treat MS patients, while Danish and Norwegian neurologists have to use other anti-CD20 drugs, as ocrelizumab, in most of the cases.In this paper, we review the pharmacokinetics, pharmacodynamics, clinical efficacy, safety profile and cost effectiveness aspects of RTX for the treatment of MS. Particularly, with the approval of new anti-CD20 DMTs, the recent worldwide COVID-19 emergency and the possible increased risk of infection with this class of drugs, this review sheds light on the use of RTX as an alternative treatment option for MS management, while commenting the gaps of knowledge regarding this drug.
Project description:OBJECTIVE: We aimed to describe hospitalizations in the multiple sclerosis (MS) population, and to evaluate temporal trends in hospitalizations in the MS population compared to the general population. METHODS: Using population-based administrative data, we identified 5,797 persons with MS and a matched general population cohort of 28,769 persons. Using general linear models, we evaluated temporal trends in hospitalization rates and length of stay in the 2 populations over the period 1984-2011. RESULTS: In 1984 the hospitalization rate was 35 per 100 person-years in the MS population and 10.5 in the matched population (relative risk [RR] 3.33; 95% confidence interval: 1.67-6.64). Over the study period hospitalizations declined 75% in the MS population but only 41% in the matched population. The proportion of hospitalizations due to MS declined substantially from 43.4% in 1984 to 7.8% in 2011. The 3 most common non-MS-related reasons for admission in the MS population were diseases of the digestive, genitourinary, and circulatory systems. Admissions for bacterial pneumonia, influenza, urinary tract infections, and pressure ulcers occurred more often in the MS population than in the general population, while admissions for circulatory system disease and neoplasms occurred less often. Older age, male sex, and lower socioeconomic status were associated with increased hospitalization rates for non-MS-related reasons. CONCLUSIONS: Although hospitalization rates have declined dramatically in the MS population over the last quarter century, they remain higher than in the general population. Admissions for MS-related reasons now constitute only a small proportion of the reasons for hospitalization.
Project description:This article addresses the concern regarding late-onset dose-limiting toxicities (DLT), moderate toxicities below the threshold of a DLT and cumulative toxicities that may lead to a DLT, which are mostly disregarded or handled in an ad hoc manner when determining the maximum tolerated dose (MTD) in dose-finding cancer clinical trials. An extension of the Time-to-Event Continual Reassessment Method (TITE-CRM) which allows for the specification of toxicity constraints on both DLT and moderate toxicities, and can account for partial information is proposed. The method is illustrated in the context of an Erlotinib dose-finding trial with low DLT rates, but a significant number of moderate toxicities leading to treatment discontinuation in later cycles. Based on simulations, our method performs well at selecting the dose level that satisfies both the DLT and moderate-toxicity constraints. Moreover, it has similar probability of correct selection compared to the TITE-CRM when the true MTD based on DLT only and the true MTD based on grade 2 or higher toxicities alone coincide, but reduces the probability of recommending a dose above the MTD.
Project description:ObjectiveInaccessibility of the inflammation compartmentalized to the central nervous system (CNS) may underlie the lack of efficacy of immunomodulatory treatments in progressive multiple sclerosis (MS). The double blind combination of Rituximab by IntraVenous and IntraThecAl injection versus placebo in patients with Low-Inflammatory SEcondary progressive MS (RIVITALISE; NCT01212094) trial was designed to answer: (1) Whether an induction dose of intravenous and intrathecal rituximab efficiently depletes CNS B cells? and (2) If so, whether this leads to global inhibition of CNS inflammation and slowing of CNS tissue destruction?MethodsPatients aged 18-65 years were randomly assigned to rituximab or placebo. Protocol-stipulated interim analysis quantified the efficacy of B-cell depletion.ResultsThe efficacy on cerebrospinal fluid (CSF) biomarkers failed to reach criteria for continuation of the trial. B-cell-related CSF biomarkers (sCD21 and B-cell activating factor) changed only in the active-treatment arm. While CSF B cells were killed robustly (median -79.71%, P = 0.0176), B cells in CNS tissue were depleted inadequately (~-10-20%, P < 0.0001). Consequently, the T-cell-specific CSF biomarker sCD27 decreased slightly (-10.97%, P = 0.0005), while axonal damage marker, neurofilament light chain did not change. Insufficient saturation of CD20, lack of lytic complement, and paucity of cytotoxic CD56(dim) NK cells contribute to decreased efficacy of rituximab in the CNS.InterpretationBiomarker studies reliably quantified complementary pharmacodynamic effects of rituximab in the CNS, exposed causes for poor efficacy and determined that RIVITALISE trial would be underpowered to measure efficacy on clinical outcomes. Identified mechanisms for poor efficacy are applicable to all CNS-inflammation targeting monoclonal antibodies.
Project description:Despite the availability of a lot of effective disease-modifying drugs, multiple sclerosis (MS) (in particular the progressive forms) still represents an important unmet medical need, because of issues in terms of effectiveness, duration of response, safety, and patient compliance. An increasing body of evidence from randomized clinical trials and real-world data suggest that rituximab is a highly effective alternative in both relapsing and progressive MS, with a low discontinuation rate, related to a good benefit/risk profile, and a good compliance. To date, the use of rituximab in patients with multiple sclerosis is not in accordance with the authorized product information (off-label use). However, the use of this medicine is widespread in several countries, and in some cases, it is the most commonly used disease-modifying drug for MS subtypes. This use could be officially recognized by national regulatory authorities, according to specific procedures, to ensure equal access for patients to a safe and effective option.
Project description:Importance:Comparative real-world effectiveness studies of initial disease-modifying treatment (DMT) choices for relapsing-remitting multiple sclerosis (RRMS) that include rituximab are lacking. Objective:To assess the effectiveness and drug discontinuation rates of rituximab among patients with newly diagnosed RRMS compared with injectable DMTs, dimethyl fumarate, fingolimod, or natalizumab. Design, Setting, and Patients:This retrospective cohort study used prospectively collected data to examine specialized care of 2 Swedish county-based community samples of patients with RRMS. Patients with RRMS who received diagnoses from January 1, 2012, to October 31, 2015, who resided in Stockholm or Västerbotten Counties were identified from a Swedish multiple sclerosis registry. Main Outcomes and Measures:All reasons for drug discontinuation of initial treatment choice (main outcome) and specific reasons for switching (secondary outcomes) were analyzed with multivariable Cox regression, including propensity scores. Results:Among 494 patients (median [interquartile range] age, 34.4 [27.4-43.4] years; 158 men [32.0%]), 215 received an injectable DMT (43.5%); 86 (17.4%), dimethyl fumarate; 17 (3.4%), fingolimod; 50 (10.1%), natalizumab; 120 (24.3%), rituximab; and 6 (1.2%), other DMT. Regional preferences were pronounced, with 42 of 52 (81%) and 78 of 442 (18%) receiving rituximab in Västerbotten and Stockholm, respectively. The annual discontinuation rate for rituximab, injectable DMTs, dimethyl fumarate, fingolimod, and natalizumab were 0.03, 0.53, 0.32, 0.38, and 0.29, respectively. Continued disease activity was the main reason for discontinuation of injectable DMTs, dimethyl fumarate, and fingolimod; positive John Cunningham virus serology results were the main reason for discontinuation of natalizumab. Rate of clinical relapses and/or neuroradiologic disease activity were significantly lower for rituximab compared with injectable DMTs and dimethyl fumarate, with a tendency for lower relapse rates also compared with natalizumab and fingolimod. The annual discontinuation rate of initial treatment choice was significantly lower in Västerbotten compared with Stockholm (0.09 and 0.37, respectively). Conclusions and Relevance:Rituximab was superior to all other DMT in terms of drug discontinuation and displayed better clinical efficacy compared with injectable DMTs and dimethyl fumarate with borderline significance compared with natalizumab and fingolimod. The county where rituximab constituted the main initial treatment choice displayed better outcomes in most measured variables. Collectively, our findings suggest that rituximab performs better than other commonly used DMTs in patients with newly diagnosed RRMS.
Project description:ObjectiveTo compare the duration of birth hospitalization in mothers with multiple sclerosis (MS) and their newborns relative to the general population and to investigate the impact of MS-related clinical factors on the length of birth hospitalization stays.MethodsData from the British Columbia Perinatal Database Registry and the British Columbia MS database were linked in this retrospective cohort study. The duration of birth hospitalization in mothers with MS and their newborns (n = 432) were compared with a frequency-matched sample of the general population (n = 2,975) from 1998 to 2009. Clinical factors investigated included disease duration and disability, as measured by the Expanded Disability Status Scale. A multivariable model (generalized estimating equations) was used to analyze the association between MS and duration of birth hospitalization, adjusting for factors such as maternal age, diabetes, hypertension, and consecutive births to the same mother. Additional analyses included propensity score matching to further balance cohort characteristics.ResultsCompared with the general population, the duration of birth hospitalization was not statistically or clinically different for mothers with MS or their newborns (median differences = +1.5 and +2.1 hours, respectively; adjusted p > 0.4). Lengths of birth hospitalization were not significantly associated with disease duration (adjusted p > 0.7) or level of disability (adjusted p > 0.5). Findings remained virtually unchanged after propensity score matching.ConclusionsBirth hospitalization has been understudied in women with MS. Contrary to existing studies, we found that MS was not associated with a longer birth hospitalization. This study provides assurance to expectant mothers with MS, their families, and health care providers.
Project description:Previous studies have demonstrated that the chimeric monoclonal antibody rituximab significantly reduces clinical and radiological disease activity in relapsing-remitting multiple sclerosis as early as 4?weeks after the first administration. The exact mechanisms leading to this rapid effect have not yet been clarified. The aim of this positron emission tomography study was to assess central nervous system penetration as a possible explanation, using zirconium-89-labelled rituximab. No evidence was found for cerebral penetration of [89Zr]rituximab.